Compositions and methods for treating neuropsychiatric disorders

ABSTRACT

As described below, the present invention features compositions and methods for treating brain and/or behavioral health disorders and their associated symptoms.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of PCT Patent Application No.PCT/US21/27641, filed Apr. 16, 2021, which claims the benefit of andpriority to U.S. Provisional Application Nos. 63/011,932, filed Apr. 17,2020, and 63/111,156, filed Nov. 9, 2020, the entire contents of each ofwhich are incorporated herein by reference in their entireties.

BACKGROUND

Brain and behavioral health disorders are the number one cause ofdisability worldwide. Brain and behavioral health disorders include allof the major disorders that belong to neurology, psychiatry andpsychology subspecialties. Anxiety, apathy, cognitive difficulty,depression, fatigue, headache, insomnia, irritability, pain (e.g., bodypain), and psychosis are ten cardinal symptoms caused by brain andbehavioral health disorders. Individually, these symptoms are disablingfeatures of these disorders, causing loss of function.

All of the ten cardinal symptoms of brain and behavioral healthdisorders are difficult to treat because most, if not all, people withbrain and behavioral disorders suffer from more than one cause of thesesymptoms. In real clinical practice, the cause of a symptom could be dueto neurology, psychiatry, and/or psychological factors. However,patients seek independent treatment for their symptoms. Anxiety,depression, and psychosis are typically treated by a psychiatrist.Headache, pain, and cognitive difficulty is often treated by aneurologist. Irritability, apathy, insomnia and fatigue are oftentreated by psychologists or primary care doctors. Anxiety is an exampleof a symptom that is disabling, difficult to treat and multifactorial.Somatic anxiety (hypersensitivity to stimulation) is an example of aneurological cause of anxiety, often related to migraine. Excessiveshyness is an example of a psychological cause of anxiety, often relatedto social phobia. Excessive worry is an example of a psychiatric causeof anxiety, often related to generalized anxiety disorder orobsessive-compulsive disorder.

Despite the fact that the ten cardinal disabling symptoms (i.e.,anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, pain (e.g., body pain), and psychosis) of brainand behavioral health disorders, in real clinical practice, aremulti-factorial, current FDA-approved treatments typically target onecomponent of a disorder at a time. For example, selective serotoninreuptake inhibitors (“SSRI's”), which are the first-line treatment foranxiety disorders, were designed specifically to target serotonergicmechanisms of anxiety. The effectiveness of these medications in and ofthemselves has proven to be limited. Cognitive behavioral therapy isdesigned specifically to address psychological components of anxiety.Patients receiving both medication and cognitive behavioral therapy arepredicted to have better outcomes than those receiving one targetedtreatment or the other. Even with cognitive behavioral therapy andmedication, treatment success remains limited, suggesting thatneurological underpinnings of anxiety remain untreated in the majorityof patients seeking relief for anxiety.

No current treatments have been designed to address the multi-factorialfeatures associated with the most disabling symptoms of brain andbehavioral health disorders. Accordingly, new treatments that addressbrain and behavioral health disorders and their symptoms are urgentlyneeded.

SUMMARY

As described below, the present invention features compositions andmethods for treating brain and/or behavioral health disorders and theirassociated symptoms.

The invention provides novel combination therapies comprising an agentthat targets the adrenergic system (e.g., anipamil, devapamil,falipamil, gallopamil, tiapamil, and verapamil) and an agent thattargets the renin angiotensin aldosterone system (RAAS) (e.g.,candesartan, telmisartan). While such agents have been individuallyapproved by the FDA for the treatment of cardiovascular disease, theyhave not previously been combined, nor have they been used for thetreatment of any brain and/or behavioral health disorder. In anembodiment, the invention provides a combination therapy featuring afirst agent selected from one or more of anipamil, devapamil, falipamil,gallopamil, tiapamil, and verapamil and a second agent selected from oneor more of candesartan and telmisartan. Without intending to be bound bytheory, the combinations provided herein create novel, synergistic,equilibrating effects on whole brain cerebral blood flow via modulationof stress-induced hormones in both the body and brain.

These combinations are effective in treating brain and/or behavioralhealth disorders, and their associated symptoms, including but notlimited to anxiety, apathy, cognitive difficulty, depression, fatigue,headache, insomnia, irritability, pain (e.g., body pain), and psychosis.

In one aspect, the invention features a therapeutic combination for thetreatment of a brain and/or behavioral health disorder or symptomthereof. The combination contains an effective amount of a first agentthat targets the adrenergic system and an effective amount of a secondagent that targets the renin angiotensin aldosterone system.

In another aspect, the invention features a therapeutic combination forthe treatment of anxiety disorder containing an effective amount of afirst and a second agent. The first agent is verapamil and the secondagent is telmisartan, and the first and second agents are provided in anextended release formulation.

In another aspect, the invention features a method for treating asubject having a brain or behavioral health disorder. The methodinvolves administering to the subject a combination therapy containing afirst agent that targets the adrenergic system and a second agent thattargets the renin angiotensin aldosterone system, thereby treating thebrain or behavioral health disorder.

In another aspect, the invention features a method for treating ananxiety disorder involving administering to a subject a therapeuticcombination containing effective amounts of a first and a second agent.The first agent is verapamil and the second agent is telmisartan. Thefirst and second agents are provided in an extended release formulation.

In another aspect, the invention features a method of increasingadvancement of a subject along Maslow's hierarchy of needs. The methodinvolves administering to the subject a therapeutically effective amountof a first agent and of a second agent. The first agent altersmetabolism and/or blood flow associated with the adrenergic system andthe second agent alters metabolism and/or blood flow associated with thebrain renin angiotensin aldosterone system, thereby increasingadvancement of the subject along Maslow's hierarchy of needs. Theincrease in advancement is relative to a reference.

In one aspect, the invention features a pharmaceutical compositioncontaining effective amounts of a first and second agent and apharmaceutically acceptable excipient. The first agent is selected fromone or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil and the second agent is selected from one or more oftelmisartan and candesartan. In embodiments, the pharmaceuticalcomposition further contains magnesium oxide.

In another aspect, the invention features a kit containing a therapeuticcombination containing a therapeutic combination containing a first andsecond agent. The first agent is selected from one or more of anipamil,devapamil, falipamil, gallopamil, tiapamil, and verapamil and the secondagent is selected from one or more of telmisartan and candesartan. Thekit also contains instructions for the use of the combination for thetreatment of a brain and/or behavioral health disorder or a symptomthereof.

In any of the above aspects, the first agent has calcium channelblocking activity and the second agent has angiotensin II receptorblocking activity. In any of the above aspects, the first agent isselected from one or more of anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil. In any of the above aspects, the first agent isverapamil. In any of the above aspects, the second agent is telmisartanor candesartan. In any of the above aspects, the second agent istelmisartan. In any of the above aspects, the second agent iscandesartan.

In any of the above aspects, the combination is labeled for thetreatment of a brain and/or behavioral health disorder. In any of theabove aspects, the combination is labeled for the treatment of a symptomof a brain and/or behavioral health disorder selected from one or moreof anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, pain and psychosis.

In any of the above aspects, the effective amount of the first agent isfrom about 120 mg to about 720 mg and the effective amount of the secondagent is from about 45 mg to about 180 mg. In any of the above aspects,the effective amount of the first agent is about 288 mg and theeffective amount of the second agent is about 96 mg.

In any of the above aspects, the mass ratio of the first agent to thesecond agent is from about 2:1 to about 5:1. In any of the aboveaspects, the mass ratio of the first agent to the second agent is about2:1. In any of the above aspects, the amount of first agent is fromabout 1 to about 4 times the amount of the second agent. In any of theabove aspects, the amount of first agent is from about 1 to about 4times the amount of the second agent.

In any of the above aspects, the agents are formulated together orseparately.

In any of the above aspects, the combination therapeutic is administeredonce daily. In any of the above aspects, the combination therapeutic isadministered twice daily.

In any of the above aspects, the agents are administered simultaneously.In any of the above aspects, the agents are administered sequentially.

In any of the above aspects, the administration is associated with analteration in cerebral metabolism or cerebral blood flow. Inembodiments, cerebral blood flow is altered in one or more of thetelencephalon, the diencephalon, and the mesencephalon. In embodiments,the alteration in regional cerebral blood flow is associated with theestablishment of hemodynamic equilibrium in a region of the brain.

In any of the above aspects, the method increases a primary outcomeselected from one or more of cognitive function, life satisfaction, thesubject's sense of meaning and purpose, the subject's sense of emotionalor instrumental support, friendship, and life satisfaction.

In any of the above aspects, the therapeutic combination furthercontaining magnesium oxide. In any of the above aspects, the therapeuticcombination contains at least about 150 mg magnesium oxide. In any ofthe above aspects, the method further involves administering magnesiumoxide to the subject. In embodiments, at least about 150 mg magnesiumoxide is administered to the subject daily.

Other features and advantages of the presently disclosed embodimentswill be apparent from the detailed description, and from the claims.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them below, unlessspecified otherwise.

By “agent” is meant any small molecule chemical compound. Exemplaryagents include but are not limited to anipamil, candesartan, devapamil,falipamil, gallopamil, telmisartan, tiapamil, and verapamil.

By “ameliorate” is meant decrease, suppress, attenuate, diminish,arrest, or stabilize the development or progression of a disease.

By “alteration” is meant a positive or negative change. As used herein,an alteration includes a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% change. The changecan be an increase or a reduction. The measured quantity can be anamount of regional cerebral blood flow. The measured quantity can be aquantitative assessment of the magnitude of a symptom of a disease(e.g., anxiety, apathy, cognitive difficulty, depression, fatigue,headache, insomnia, irritability, pain (e.g., body pain), or psychosis).In some embodiments, an alteration is a reduction in a symptomassociated with a brain and/or behavioral health disorder. In someembodiments, an alteration is an increase in function associated withthe treatment of a brain and/or behavioral health disorder.

By “ameliorate” is meant decrease, suppress, attenuate, diminish,arrest, or stabilize the development or progression of a disease.

By “analog” is meant a molecule that is not identical to a molecule ofinterest, but that has analogous functional and/or structural features.In some embodiments, an analog is an agent that targets the adrenergicsystem. In some embodiments, an analog is an agent that targets therenin angiotensin aldosterone system.

By “anipamil” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,anipamil has calcium channel blocking activity.

By “candesartan” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,candesartan has angiotensin II receptor blocking activity.

By “cerebral metabolism” is meant the rate of metabolism in the brain ora region thereof. Cerebral metabolism is measured using any of a varietyof methods available to a practitioner including, as non-limitingexamples thereof, X-ray computed tomography (CT), positron emissiontomography (PET), near-infrared spectroscopy (NIRS), magnetic resonanceimaging (MRI), and those methods provided herein. In embodiments, anincrease in metabolism in a region of the brain is associated with anincrease in blood flow to the region. Cerebral blood flow is measuredusing any of a variety of methods available to a practitioner including,as non-limiting examples thereof, single-photon emission computedtomography (SPECT), positron emission tomography (PET), functional MRI(fMRI), arterial spin labeling (ASL) MRI, transcranial Dopplerultrasound imaging (i.e., sonography), phase-contrast MRI, andnear-infrared spectroscopy (NIRS).

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean “includes,” “including,” and the like; “consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. Patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited is not changed by the presenceof more than that which is recited, but excludes prior art embodiments.Any embodiments specified as “comprising” a particular component(s) orelement(s) are also contemplated as “consisting of” or “consistingessentially of” the particular component(s) or element(s) in someembodiments.

By “consist essentially” it is meant that the ingredients include onlythe listed components along with the normal impurities present incommercial materials and with any other additives present at levelswhich do not affect the operation of the disclosure, for instance atlevels less than 5% by weight or less than 1% or even 0.5% by weight.

By “decrease” is meant a negative alteration.

By “devapamil” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In an embodiment,devapamil has calcium channel blocking activity.

By “disease” is meant any condition or disorder that damages orinterferes with the normal function of a cell, tissue, or organ. Inembodiments, the disease or disorder is a neuropsychiatric disorder,examples of which include brain and/or behavioral health disorders andsymptoms thereof. Non-limiting examples of brain and behavioral healthdisorders include affective disorders, anxiety disorders,neurodegenerative disorders, neurodevelopmental disorders, psychoticdisorders, personality disorders, migraine disorders and somatoformdisorders. Examples of affective disorders include bipolar disorder,cyclothymia, depression, dysthemia, generalized anxiety disorder, majordepressive disorder, obsessive compulsive disorder, postpartumdepression, post-traumatic stress disorder (PTSD), phobias, and seasonalaffective disorder. Examples of anxiety disorders include panicdisorder, social anxiety disorder, post-traumatic stress disorder,obsessive compulsive disorder, and specific phobia. Examples ofneurodegenerative disorders include Alzheimer's disease and Parkinson'sdisease. Examples of neurodevelopmental disorders include autismspectrum disorder, attention deficit hyperactive disorder (ADHD) andlearning disorders. Examples of psychotic disorders includeschizophrenia, schizoaffective disorder, and major depression withpsychosis. Examples of personality disorders include paranoid, schizoid,schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant,dependent, and obsessive-compulsive personality disorder. Examples ofmigraine-related disorders include migraine with aura, migraine withoutaura, acephalgic migraine, and basilar migraine. Examples of somatoformdisorders include somatization disorder, hypochondriasis, conversiondisorder, body dysmorphic disorder and chronic pain. The symptomsassociated with the disease are selected from one or more of the “tencardinal symptoms” associated with brain and behavioral healthdisorders, including but not limited to anxiety, apathy, cognitivedifficulty, depression, fatigue, headache, insomnia, irritability, pain(e.g., body pain), and psychosis. In embodiments, the disease isassociated with altered regional cerebral blood flow relative to areference (e.g., the blood flow present in a healthy control brain). Thedisease can be a brain or behavioral health disorder as defined above.

By “effective amount” is meant an amount of an agent sufficient to treata disease or disorder. In one embodiment, an effective amount of acombination therapy described herein is sufficient to treat a brainand/or behavioral disorder or a symptom thereof, or to effect animprovement in a primary outcome (e.g., increase cognitive function,life satisfaction, the subject's sense of meaning and purpose, thesubject's sense of emotional or instrumental support, friendship, andlife satisfaction).

By “falipamil” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,falipamil has calcium channel blocking activity.

By “gallopamil” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,gallopamil has calcium channel blocking activity.

By “hemodynamic equilibrium” is meant a state of balance with respect torelative blood flow rates among corresponding regions of the brain. Inembodiments, hemodynamic equilibrium is associated with approximatelyequal relative blood flow rates and/or metabolic activity among theregions.

By “increases” is meant a positive alteration.

As used herein, “obtaining” as in “obtaining an agent” includessynthesizing, purchasing, or otherwise acquiring the agent.

As used herein, the terms “prevent,” “preventing,” “prevention,”“prophylactic treatment” and the like refer to reducing the probabilityof developing a disorder or condition in a subject, who does not have,but is at risk of or susceptible to developing a disorder or condition.

By “reduces” is meant a negative alteration.

By “subject” is meant a mammal. Non-limiting examples of mammals includea human or non-human mammal, such as a bovine, equine, canine, ovine,feline, or rodent.

By “reference” is meant a standard or control condition. In oneembodiment, the effect of an agent on a cell is compared to the effectof the agent on a control cell. In embodiments, the reference is ahealthy subject. In embodiments, a clinical feature of subject having abrain or behavioral disorder is compared to a reference clinical featurepresent in a healthy subject. The healthy subject is a subject nothaving a disorder or condition of interest. In some embodiments, thereference is an untreated patient or a subject prior to treatment orprior to an alteration in treatment.

By “region of the brain” is meant a portion of the brain. Inembodiments, the portion of the brain contains one or more of thetelencephalon, the diencephalon, and the mesencephalon. The region cancontain all three of the telencephalon, the diencephalon, and themesencephalon.

By “simultaneous administration” is meant administering concurrently.

By “sequential administration” is meant administered at separate pointsin time. For example, one or more agents are administered sequentiallyif the administration is separated by minutes, hours, or days. Forexample, in sequential administration a first agent is administered 15,30, 45, or 60 minutes prior to the administration of one or moreadditional agents. In another example of sequential administration, afirst agent is administered 1, 2, 3, 4, 5, 6, 12, or 24 hours prior tothe administration of the second agent. In yet another example ofsequential administration, a first agent is administered 1, 2, 3, 4, 5,6, or 7 days prior to the administration of the second agent.

By “telmisartan” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,telmisartan has angiotensin II receptor blocking activity.

“Therapeutic agent” means a substance that has the potential ofaffecting the function of an organism. Such a compound is, for example,a naturally occurring, semi-synthetic, or synthetic agent. For example,an agent is a drug that targets a specific function of an organism. Atherapeutic agent can decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of disease, disorder, orcondition. A therapeutic agent is associated with an alteration inregional cerebral blood flow in a subject. Non-limiting examples oftherapeutic agents described herein include anipamil, candesartan,devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil,as well as derivatives, analogs, and functional equivalents of suchagents. In embodiments, a therapeutic combination features a first agentselected from one or more of anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil and a second agent selected from one or more ofcandesartan and telmisartan.

By “effective amount” is meant the amount of an agent required to reduceor ameliorate a symptom of a disease relative to a reference. Theeffective amount of active compound(s) (e.g., anipamil, candesartan,devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil)used to practice the present invention for therapeutic treatment of adisease varies depending upon the manner of administration, the age,body weight, and general health of the subject. Ultimately, theattending physician or veterinarian will decide the appropriate amountand dosage regimen. Such amount is referred to as an “effective” amount.The symptom is selected from one or more of “ten cardinal symptoms”associated with brain and behavioral health disorders: anxiety, apathy,cognitive difficulty, depression, fatigue, headache, insomnia,irritability, pain (e.g., body pain), and psychosis. In embodiments, thetherapeutically effective amount is the amount of an agent orcombination of agents necessary

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

By “tiapamil” is meant a compound having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,tiapamil has calcium channel blocking activity.

As used herein, the terms “treat,” treating,” “treatment,” and the likerefer to reducing or ameliorating a disease and/or symptoms associatedtherewith. It will be appreciated that, although not precluded, treatinga disorder or condition does not require that the disorder, condition orsymptoms associated therewith be completely eliminated.

By “verapamil” is meant an agent having the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments,verapamil has calcium channel blocking activity.

Unless specifically stated or obvious from context, as used herein, theterm “or” is understood to be inclusive. Unless specifically stated orobvious from context, as used herein, the terms “a”, “an”, and “the” areunderstood to be singular or plural.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example within 2 standard deviations of the mean. About can beunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear fromcontext, all numerical values provided herein are modified by the termabout.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable or aspect herein includes that embodiment as any singleembodiment or in combination with any other embodiments or portionsthereof.

Any compositions or methods provided herein can be combined with one ormore of any of the other compositions and methods provided herein. Wherevarious mechanisms of action, hypotheses, or theories are discussedthroughout the application, these are not intended to be limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1J are graphs illustrating differences in symptoms in 76patients before vs. after combination therapy with telmisartan andverapamil. Combination therapy comprised either 120 mg or 180 mg ofverapamil twice per day with either 40 mg or 80 mg of telmisartan twiceper day. FIG. 1A is a graph showing lower overall symptomatology betweenpatients on vs. off the combination therapy. FIG. 1B is a graph showinglower self-reported anxiety in patients on vs. off the combinationtherapy. FIG. 1C is a graph showing lower self-reported depression inpatients on vs. off the combination therapy. FIG. 1D is a graph showinglower self-reported irritability in patients on vs. off the combinationtherapy. FIG. 1E is a graph showing lower self-reported apathy inpatients on vs. off the combination therapy. FIG. 1F is a graph showinglower self-reported fatigue in patients on vs. off the combinationtherapy. FIG. 1G is a graph showing lower self-reported body pain inpatients on vs. off the combination therapy. FIG. 1H is a graph showingless severe self-reported insomnia severity in patients on vs. off thecombination therapy. FIG. 1I is a graph showing decrease inself-reported headache in patients on vs. off the combination therapy.FIG. 1J is a graph showing a decrease in self-reported cognitivedifficulty in patients on vs. off the combination therapy.

FIGS. 2A-2F illustrate differences in standardized psychosocial outcomesbetween patients on vs. off the combination therapy. FIG. 2A is a graphshowing higher general life satisfaction in patients on vs. offcombination therapy. FIG. 2B is a graph showing greater meaning andpurpose in patients on vs. off combination therapy. FIG. 2C is a graphshowing higher emotional support in patients on vs. off treatment withcombination therapy. FIG. 2D is a graph showing higher instrumentalsupport in patients on vs. off treatment with combination therapy. FIG.2E is a graph showing higher friendship in patients on vs. off treatmentwith combination therapy. FIG. 2F is a graph showing lower loneliness inbetween patients on vs. off combination therapy.

FIGS. 3A and 3B illustrate differences in outcomes between patientsreceiving the combination treatment and patients receiving onlytelmisartan. FIG. 3A is a graph showing the difference in lifesatisfaction as measured by the NIH Toolbox between patients receivingthe combination therapy and patients receiving telmisartan only. FIG. 3Bis a graph showing the difference in anger (hostility) as measured bythe NIH Toolbox between patients receiving the combination therapy andpatients receiving telmisartan only.

FIGS. 4A and 4B illustrate differences in outcomes between patientsreceiving the combination treatment and patients receiving onlyverapamil. FIG. 4A is a graph showing the difference in self-efficacy asmeasured by the NIH Toolbox between patients receiving the combinationtherapy and patients receiving telmisartan only. FIG. 4B is a graphshowing the difference in anger (aggression) as measured by the NIHToolbox between patients receiving the combination therapy and patientsreceiving verapamil only.

FIG. 5 is a diagram presenting a proposed mechanism of action of acomposition containing verapamil and telmisartan. The figure depicts thebrain in its embryological state before telencephalon, diencephalon andmesencephalon develop into cortex, subcortex and brainstem structures.

FIG. 6 is a schematic illustrating how a composition containingverapamil and telmisartan is hypothesized to enable progressiveequilibration of cerebral blood flow as patients make psychosocialprogress along Maslow's Hierarchy of Needs.

FIG. 7 is a diagram showing bidirectional changes in Weberlateralization in patients who either start, stop or change dose of acomposition containing verapamil and telmisartan. Of the individualsthat had a change in treatment, 83% ( 15/18) had a change in their Weberlateralization. Of those that had no change in treatment, 20% (⅕)reported a change in Weber lateralization. This difference in Weberlateralization changes between patients who had vs. did not have achange in treatment was statistically significant (p=0.006).

FIG. 8 is a plot showing bi-directional influences of a compositioncontaining verapamil and telmisartan on patient blood pressure. For the29 patients with high blood pressure, the pre-post decrease to withinnormal range was statistically significant (p=0.0001). For the 11patients with low blood pressure, the pre-post increase to within normalrange was statistically significant (p=0.001). For the 29 patients withnormal blood pressure, the pre-post change was not statisticallysignificant (p=0.553).

FIG. 9 is a diagram presenting a proposed method by which compositionsof the present invention comprising a first agent selected from one ormore of anipamil, candesartan, devapamil, falipamil, gallopamil,telmisartan, tiapamil, and verapamil and a second agent selected fromone or more of candesartan and telmisartan can affect dynamic changescaused by psychological stress. Depending on the structural make-up ofthe brain, psychological stress can cause the body to respond withdynamic adaptations in adrenalin and angiotensin, especially in settingsof brain energy supply/demand mismatches. These adaptations causechanges in functional connectivity of the brain, which modulatesmetabolic demand in selectively vulnerable brain regions. In thepresence of the compositions, the dynamic changes cause by psychologicalstress on functional connectivity are regulated, which results in lowerneuropsychiatric symptomatology.

DETAILED DESCRIPTION

The invention features compositions and methods that are useful for thetreatment of brain and/or behavioral health disorders, and theirassociated symptoms.

The invention is based, at least in part, on the discovery that acombination therapy comprising an agent that targets the adrenergicsystem (e.g., verapamil or other compounds with calcium channel blockingactivity) and an agent that targets the renin angiotensin aldosteronesystem (RAAS) (e.g., telmisartan) effectively treated brain and/orbehavioral health disorders and significantly reduced associatedsymptoms. In view of this surprising discovery, one of skill in the artwould understand that any agent that targets the RAAS (e.g.,telmisartan, candesartan) could be combined with any agent that targetsthe adrenergic system (e.g., anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil) for the treatment of brain and/or behavioralhealth disorders and their associated symptoms. In particular, asreported in detail below, verapamil and telmisartan were effective atreducing or eliminating anxiety, apathy, cognitive difficulty,depression, fatigue, headache, insomnia, irritability, and chronic pain.Significantly, verapamil and telmisartan not only reduced such symptomsin treated subjects, but also produced a number of positive changes insuch subjects, including an increase in general life satisfaction andmeaning and purpose. Without intending to be bound by theory, it islikely that the combination of verapamil and telmisartan simultaneouslytargeted stress-induced hormones in both the body and the brain thatcollectively influence brain function.

Brain and Behavioral Disorders

Collectively, brain and behavioral disorders are the number one cause ofdisability worldwide. Achieving comprehensive remission, across thespectrum of so many different symptoms, is difficult for most patients,doctors and families because in real clinical practice, patients havemultiple co-morbid diagnoses. Treating a patient with multipleco-morbidities requires separate individual treatment for each disorder,which increases complexity, inflates cost and lowers safety of care.

Brain and behavioral health disorders, at least partially due to havingmultiple components, result in serious psychosocial issues thatnegatively impact a patient's quality of life. However, currenttreatments are designed to treat only a single (e.g., neurological)component.

Although brain and behavioral health disorders are a clinically diversegroup of disorders, abnormal functional connectivity represents ashared, common pathological framework. Regardless of the disorder, twoindependent systems, the adrenergic system and the brain reninangiotensin aldosterone system, directly influence functionalconnectivity. Across these disorders, abnormalities within one networktend to disrupt the function of related networks. For example, anxietydisorders and chronic pain can be classified, together, as reactivedisorders, each featuring atypical connectivity between sensorimotor andsalience networks. In fact, successful treatment of symptoms for manybrain and behavioral disorders has been shown to be associated withnormalization of atypical patterns of regional cerebral blood flow.

Non-limiting examples of brain and behavioral health disorders includeaffective disorders, anxiety disorders, neurodegenerative disorders,neurodevelopmental disorders, psychotic disorders, personalitydisorders, migraine disorders and somatosensory somatoform disorders.Examples of affective disorders include bipolar disorder, cyclothymia,depression, dysthemia, generalized anxiety disorder, major depressivedisorder, obsessive compulsive disorder, postpartum depression,post-traumatic stress disorder (PTSD), phobias, and seasonal affectivedisorder. Examples of anxiety disorders include panic disorder, socialanxiety disorder, post-traumatic stress disorder, obsessive compulsivedisorder and specific phobia. Examples of neurodegenerative disordersinclude Alzheimer's disease and Parkinson's disease. Examples ofneurodevelopmental disorders include autism spectrum disorder, attentiondeficit hyperactive disorder (ADHD) and learning disorders. Examples ofpsychotic disorders include schizophrenia, schizoaffective disorder andmajor depression with psychosis. Examples of personality disordersinclude paranoid, schizoid, schizotypal, antisocial, borderline,histrionic, narcissistic, avoidant, dependent and obsessive-compulsivepersonality disorder. Examples of somatosensory disorders includechronic pain and migraine-related disorders include migraine with aura,migraine without aura, acephalgic migraine, and basilar migraine.Examples of somatoform disorders include somatization disorder,hypochondriasis, conversion disorder, body dysmorphic disorder andchronic pain. The symptoms associated with the disease is selected fromone or more of the “ten cardinal symptoms” associated with brain andbehavioral health disorders, including but not limited to anxiety,apathy, cognitive difficulty, depression, fatigue, headache, insomnia,irritability, body pain and psychosis. Such symptoms are measured usingany of a variety of methods available to a practitioner, non-limitingexamples of which are presented in Brenes, “Anxiety, Depression, andQuality of Life in Primary Care Patients”, Prim Care Companion J ClinPsychiatry, 9:437-443 (2007) and in Julian, “Measures of Anxiety”,Arthritis Care Res, 63:1-11 (2011).

No current treatments for the above listed disorders are designed toaddress the functional connectivity abnormalities that are germane tothe disorders. Selective serotonin reuptake inhibitors (“SSRI's”) havelimited effectiveness for anxiety. Even with cognitive behavioraltherapy and medication, treatment success remains limited. Since SSRI'sdo not treat symptoms caused by common anxiety co-morbidities such asADHD, disability due to co-morbidities remains untreated in the majorityof patients seeking relief for anxiety. For patients with ADHD,stimulants are not effective for, and can often exacerbate, co-morbidmood disorders. These are critical treatment gaps because the symptomscaused by psychiatric co-morbidities are often the most disabling.Moreover, current controlled treatment options, specificallybenzodiazepines, stimulants and opiates, are dangerous due toexacerbation of co-morbid mood disorders, addiction and lethal overdose.

Combination Therapies

Certain existing pharmaceuticals that influence the adrenergic systemand the brain renin angiotensin aldosterone system and never previouslyused in combination can be combined to create novel, synergistic changesin cerebral blood flow that translate into desirable clinical outcomes.Combination treatments of the present invention involve, for example,administering to a subject a combination of two or more agents selectedfrom previously FDA-approved cardiovascular medications. The inventionfeatures combinations containing verapamil and telmisartan, verapamiland candesartan, as well as candesartan and/or telmisartan incombination with one or more of anipamil, devapamil, falipamil,gallopamil, tiapamil, and verapamil.

Individually, agents are selected to target the renin angiotensinaldosterone system and the adrenergic system. Telmisartan andcandesartan, individually or in combination, balance the severity of theangiotensin response because they block angiotensin 2 receptors. Notwishing to be bound by theory, anipamil, devapamil, falipamil,gallopamil, tiapamil, and verapamil, individually or in combination,balance the severity of the adrenalin response because they influenceoutput of norepinephrine from the midbrain. Since both the adrenergicsystem and the brain RAAS interact to modulate functional connectivity,combining agents that target each system independently createssynergistic effects resulting in novel treatment effects.

A novel treatment is presented herein that ameliorates the psychiatric,psychological and neurological components of disorders that manifest asone or more of the ten cardinal neuro-psychiatric symptoms (i.e.,anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, pain (e.g., body pain), and psychosis),regardless of the underlying diagnosis. Without intending to be bound bytheory, compositions and/or dosage forms of the present inventioncontaining a therapeutic combination (e.g., verapamil and telmisartan,verapamil and candesartan, and candesartan and/or telmisartan incombination with one or more of anipamil, devapamil, falipamil,gallopamil, tiapamil, and verapamil) target stress-induced hormones indifferent regions of the brain simultaneously. The combinations ofagents described herein, targeting both the adrenergic and the brainRAAS simultaneously with positive pluri-network effects, has never beencontemplated or studied until now.

Administration to a subject of the compositions and dosage forms of thepresent invention containing a first agent selected from one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil anda second agent selected from one or more of candesartan and telmisartan,delivered simultaneously or sequentially as a combination treatment, isuseful for the treatment of brain and/or behavioral disorders and theirassociated symptoms (i.e., anxiety, apathy, cognitive difficulty,depression, fatigue, headache, insomnia, irritability, body pain, andpsychosis. The combination treatments lead to positive psychosocialoutcomes which, over time, correlate with significant improvements inoverall measures of quality of life. For example, the compositions areassociated with achieving patient advances along Maslow's hierarchy ofneeds, which is comprehensive outcome in healthcare that reflects notonly symptomatology but also impact across a broad range of socialdeterminants of health. In some embodiments, therapeutic combinationsdescribed herein positively affect the well-being of a subjectundergoing treatment (e.g., increasing cognitive function, increasinglife satisfaction, increasing meaning and purpose, increasing emotionalsupport, increasing instrumental support, increasing friendship,increasing life satisfaction).

Pharmacological Effects

Without intending to be bound by theory, the pharmacological effects ofcompositions comprising a first agent selected from one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil anda second agent selected from one or more of candesartan and telmisartanrelate to the physiology of adrenalin and brain renin angiotensinaldosterone systems (RAAS). When a human senses danger, two independentbody systems change the intrinsic, functional connectivity of the brain.

The adrenergic system, also known as the sympathetic/parasympatheticsystem, influences functional connectivity via signaling by theneurotransmitter known as norepinephrine (aka “adrenalin”). Whennorepinephrine is produced in the adrenal gland, it travels to thebrain, where it binds to beta receptors. When beta receptors bindnorepinephrine, changes occur such as pupillary dilation, reduction ofpain sensation, and increased vigilance.

The brain renin angiotensin aldosterone system, also known as the brainRAAS system, influences functional connectivity via the neurotransmitterknown as angiotensin. When the angiotensin precursor is produced in thekidneys, it travels through the lung and to the brain, where it binds toangiotensin receptors. When brain angiotensin receptors bindangiotensin, changes occur in the coupling between arterioles andastrocytes, a process known as neurovascular coupling, which causesfocal changes in cerebral blood flow.

Not intending to be bound by any particular mode of action, when theadrenalin and brain RAAS systems are activated, the functionalconnectivity of the brain changes. This change in connectivity is anevolutionarily-preserved stress response system that helps the brain toadapt to metabolic demand. If maintained chronically, this can create anunequilibrated state of functional connectivity which can bedetrimental. Several factors can promote chronic disequilibrium,including the built environment, social determinants of health andindividual differences. These factors can be especially challenging forpatients with a brain and/or behavioral health disorder. Not being boundby theory, compositions comprising a first agent selected from one ormore of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil and a second agent selected from one or more of candesartanand telmisartan can re-equilibrate the changes in functionalconnectivity that are associated with a brain and/or behavioral healthdisorder.

Not wishing to be bound by theory, combination treatments involveadministering to a subject compositions comprising a first agentselected from one or more of anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil and a second agent selected from one or more ofcandesartan and telmisartan. Such combinations act on central functionalnetworks that are common to more than one neuropsychiatric disorder.Without intending to be bound by theory, the unique combination of anangiotensin II receptor blockade with a concomitant adrenergic blockadeleads to re-equilibration of distribution of cerebral blood flowparticularly in the diencephalon, which is the region of the brainimportant for social and emotional awareness. In other words, byinfluencing functional networks related to cognition (telencephalon)simultaneously with influencing functional networks related to emotion(mesencephalon), functional networks related to social cognition(diencephalon) are equilibrated. This hypothesis is based on findings ofconspicuous social changes in patients who took combination therapy. Forexample, bi-directional changes were observed in social and dressingbehavior in patients taking combination treatment. Specifically,introverted patients displayed more extraversion while on combinationtreatment, whereas extraverted patients displayed more introversionwhile on combination treatment. The results of a study described in theExamples provided herein showed an improvement in social satisfaction inpatients on combination treatment. The hypothesis that combinationtreatment leads to equilibrating effects in functional brain networks isfurther supported by analyses of results from the Weber test, performedas part of routine visits, which measures sensorineural function, whichis influenced by lateralization of the brain's auditory functionalnetwork. In the clinic, patients who initiated combination treatment orchanged from monotherapy to combination treatment displayed shifts fromone visit to the next in lateralization of the Weber test. Shifts inlateralization of the Weber test do not occur with standard of caremedications. Shifts in lateralization of the Weber do not occur whenpatients take the individual components of combination treatment.Remarkably, these shifts, like the changes in social outcomes, werebi-directional whereby some patients shifted towards the right and otherpatients shifted towards the left.

Not wishing to be bound by theory, the novel bi-directional outcomesassociated with compositions comprising a first agent selected from oneor more of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil and a second agent selected from one or more of candesartanand telmisartan suggest that combination treatment may serve aregulatory function in brain regions associated with the auditory and/orother functional brain networks. Since changes in auditory functioncorrelated with clinical improvements in social function, therapeuticcombinations described herein may affect not only auditory function, butalso the interoceptive/exteroceptive awareness as well as the socialcommunication skills that rely on auditory functioning. In fact, theauditory cortex participates directly in networks for emotionalprocessing and communication (Disability and poor quality of lifeassociated with comorbid anxiety disorders and physical conditions.Sareen J, Jacobi F, Cox B J, Belik S L, Clara I, Stein M B. Arch InternMed. 2006 Oct. 23; 166(19):2109-16. doi: 10.1001/archinte.166.19.2109).

Compositions of the Invention Modulate Adrenergic and AngiotensinFunction

Compositions comprising a first agent selected from one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil anda second agent selected from one or more of candesartan and telmisartancomprise one ingredient for adrenergic modulation and one ingredient forbrain RAAS. No pharmaceutical agents have been designed to target bothsystems simultaneously. This is a critical treatment gap because both ofthese systems interact when patients with brain and/or behavioraldisorders experience the oft-untreatable symptoms that cause suffering.

The Adrenalin and Angiotensin Systems Affect Different Functional BrainNetworks.

Without intending to be bound by theory, the effect of compositionscomprising a first agent selected from one or more of anipamil,devapamil, falipamil, gallopamil, tiapamil, and verapamil and a secondagent selected from one or more of candesartan and telmisartan dependsin part on the relative density of the adrenalin and angiotensinreceptors within each one of three phylogenetic levels of the brain. Themesencephalon is the oldest level of the brain, located at the bottom ofthe brain, just above the spinal cord. The telencephalon is the newestlevel of the brain to evolve, located at the top of the brain. Betweenthese levels is the diencephalon. Not being bound by theory, each levelof the brain contains brain regions rich with receptors that participatein several networks that subserve different neurological processes.

Since beta receptors (which bind norepinephrine) are located moredensely within mesencephalon than telencephalon, the effect ofnorepinephrine is strongest in brain networks that rely on mesencephalicbrain regions such as the brainstem. Since angiotensin receptors (whichbind angiotensin) are located more densely within telencephalon thanmesencephalon, the effect of angiotensin is strongest in brain networksthat rely on telencephalic brain regions such as the prefrontal cortex.Clinically, modulating the adrenergic system influences neuropsychiatricsymptoms (e.g., insomnia, fatigue, apathy, pain, anxiety) becausemesencephalic networks have extensive connections to body organs.Modulating the angiotensin system influences different neuropsychiatricsymptoms (e.g., cognitive impairment, headache, aura) becausetelencephalic networks have extensive connections to brain regions forsensory processing.

Each functional brain network spans different regions of the older andnewer brain. The key functional brain networks implicated in brainand/or behavioral health disorders can include the default mode network,the salience, somatosensory, visual, auditory, and limbic networks,among others. Some of these brain networks rely heavily on newer brainregions. For example, the default mode network coordinates among regionsmostly located within the telencephalon (the highest phylogeneticlevel). The salience network, on the other hand, coordinates regionswithin the mesencephalon (the lowest phylogenetically level).

TABLE 1 Functional Brain Network Regions Organized by PhylogeneticLevels Telencephalon Diencephalon Mesencephalon Salience Dorsal anteriorcingulate/ Hypothalamus Sublenticular Network paracingulate cortexDorsomedial extended Frontoinsular cortices. thalamus amygdala Anteriorinsula Ventral Putamen striatopallidum Anterior Periaqueductal temporalpole gray Substantia nigra/ventral tegmental area Default Posteriorcingulate cortex Thalamus Medial Mode Retrosplenial cortex mesencephalicNetwork VM prefrontal cortex regions AM prefrontal cortex Dorsalprefrontal cortex Temporal pole Middle temporal gyrus HippocampusParahippocampal cortex Amygdala Posterior parietal cortex Basalforebrain Somatosensory Primary somatosensory cortex Primary motorcortex Somatosensory association cortex Visual primary somatosensorycortex primary motor gyrus angular gyrus lateral occipital cortexmid-cingulate cortex anterior cingulate cortex supplementary motor areainferior frontal gyrus precentral gyrus temporal pole precuneousAuditory Bilateral superior Network temporal gyrus specifically Heschl'sgyrus and Planum temporale Limbic Hippocampus Hypothalamus AnteriorThalamic NucleiTherapeutic Combinations of the Invention Normalize Whole BrainFunctional Connectivity.

In embodiments, compositions comprising a first agent selected from oneor more of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil and a second agent selected from one or more of candesartanand telmisartan achieve pluri-network effects because equilibration inlower brain networks influences equilibration of higher networks andvice versa. The compositions comprise at least two ingredients in orderto block two different stress-related systems (adrenalin system andbrain RAAS). Each of these systems can play a key role in shiftingfunctional connectivity of the brain as needed. Not being bound bytheory, anipamil, devapamil, falipamil, gallopamil, tiapamil, verapamil,and combinations thereof interact with beta receptors withinmesencephalon (FIG. 5). Not being bound by theory, telmisartan andcandesartan interact with angiotensin receptors within telencephalon(FIG. 5).

Compositions comprising a first agent selected from one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil anda second agent selected from one or more of candesartan and telmisartan,as detailed in the Examples below, have led to clinical effects thatsuggest a regulation in functional connectivity throughout the brain.The clinical effect of the compositions included normalization not onlyof emotional, but also social and cognitive symptoms due to the uniquepluri-network effects achieved through this synergy. Not being bound bytheory, since these functions emanate from three distinct layers(diencephalon, mesencephalon and telencephalon), compositions comprisinga first agent selected from one or more of anipamil, devapamil,falipamil, gallopamil, tiapamil, and verapamil and a second agentselected from one or more of candesartan and telmisartan alterconnectivity at all three levels. The pluri-network effects of thecompositions enable patients to make swift psychosocial progress (FIG.6), which further improves whole brain connectivity (Safety NeedsMediate Stressful Events Induced Mental Disorders. Zheng Z, Gu S, Lei Y,Lu S, Wang W, Li Y, Wang F. Neural Plast. 2016; 2016:8058093. doi:10.1155/2016/8058093. Epub 2016 Sep. 21). Not being bound by theory,improvement in symptomatology referable to all three phylogenetic levelsdoes not occur when either agent is administered alone. Improvement insymptomatology referable to all three phylogenetic levels does not occurwith any known standard of care treatment.

Prevention of Brain and/or Behavioral Health Disorders, and MedicalDisorders

The pluri-network effects of compositions comprising a first agentselected from one or more of anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil and a second agent selected from one or more ofcandesartan and telmisartan discussed herein suggest that treatment withthe compositions can treat disorders (e.g., panic disorder) affectingdifferent parts of the brain at different times throughout the lifecourse. Many neuropsychiatry disorders that are amenable to preventativetreatment feature disequilibrium in more than one functional brainnetwork, suggesting that these disorders are promising candidates forprophylactic treatment with a combination therapy described herein. Forexample, chronic pain disorders, which become more refractory totreatment across the life course if unaddressed, feature abnormalitiesin visual, salience and default mode networks that can be detectableprior to the onset of significant disability. Neurodevelopmentaldisorders such as ADHD, autism spectrum disorder and learning disorder,which become more refractory to treatment across the life course ifunaddressed, feature pluri-network changes. Psychotic disorders such asschizophrenia, which becomes more refractory to treatment across thelife course if unaddressed, feature functional abnormalities in multiplebrain networks. Anxiety disorders become more refractory to treatmentacross the life course if unaddressed and show pluri-network effects,with some specific differences according to the disorder. Compositionscomprising a first agent selected from one or more of anipamil,devapamil, falipamil, gallopamil, tiapamil, and verapamil and a secondagent selected from one or more of candesartan and telmisartan are apromising preventative treatment for these conditions because they canimprove whole brain functional connectivity despite individualdifferences in network dis-equilibration among the disorders. No currenttreatments are available to prevent neuropsychiatric disorders thatworsen if left unmitigated across the life course. No research has everbeen done regarding use of such compositions for prevention ofneuropsychiatric disease or disability.

Compositions comprising a first agent selected from one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil anda second agent selected from one or more of candesartan and telmisartancan be used for prevention of neurodegenerative disease risk beginningin midlife. The compositions can cumulatively normalize cerebralmetabolism, which can be dysregulated in preclinical neurodegenerativedisease states. Different Neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease and frontotemporal lobardegeneration feature disequilibrium in different brain networks thatstem from abnormal cerebral metabolism. No current treatments areavailable that can normalize cerebral metabolism in patients at risk forneurodegenerative diseases. Use of such compositions has never beenstudied in the context of neurodegenerative disease prevention ortreatment.

Since compositions comprising a first agent selected from one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil anda second agent selected from one or more of candesartan and telmisartancan normalize whole brain cerebral connectivity, the compositions can beused for certain indications that are outside the boundaries ofneuropsychiatry (i.e., cancer, autoimmune, autonomic, among others).Dysregulated functional connectivity can affect risk for medicaldisorders because brain connectivity affects the health of the immunesystem. Specifically, medical disorders that conspicuously presentaround developmental windows (such as age 25, when the brain finishesmyelinating) are candidates for a novel, brain-based, preventativetreatment including treatment with the compositions.

Pharmaceutical Compositions

The disclosure provides pharmaceutical compositions comprising aneffective amount of a first agent selected from one or more of anipamil,devapamil, falipamil, gallopamil, tiapamil, and verapamil and aneffective amount of a second agent selected from one or more ofcandesartan and telmisartan. Such combinations may be co-formulated orformulated separately but administered concurrently or sequentially.When the first and second agents are administered in combination, theyare useful for the treatment of brain and/or behavioral health disorders(e.g., panic disorder). In some embodiments, the combination therapy isadministered to treat one or more of the ten cardinal neuro-psychiatricsymptoms (i.e., anxiety, apathy, cognitive difficulty, depression,fatigue, headache, insomnia, irritability, body pain, and psychosis).

In embodiments, the compositions of the present invention contain afirst agent selected from one or more of anipamil, devapamil, falipamil,gallopamil, tiapamil, and verapamil and a second agent selected from oneor more of candesartan and telmisartan for use in a combinationtreatment. In embodiments, the first agent is verapamil and the secondagent is telmisartan and/or candesartan. In some cases, the first agentis selected to influence the beta receptors in the mesencephalon and thesecond agent is selected to interact with angiotensin receptors in thetelencephalon. The agents can be selected so that the first agentinfluences the adrenalin system and the second agent influences thebrain renin angiotensin aldosterone system. In embodiments, thecompositions are associated with modulation of both adrenergic andangiotensin function.

In certain embodiments, the compositions of the present invention canprevent, inhibit, or disrupt, or reduce by at least 10%, 25%, 50%, 75%,or even 100% one or more of anxiety, migraine, depression, cognitivedifficulty, anger, apathy, fatigue, body pain, psychosis, and insomniathat manifest in individuals afflicted with a disorder having one ormore psychiatric, psychological and/or neurological components.

Pharmaceutically acceptable salts of anipamil, candesartan, devapamil,falipamil, gallopamil, telmisartan, tiapamil, and verapamil, orcombinations thereof are contemplated herein for the treatment of one ormore of the ten cardinal neuropsychiatric symptoms (i.e., anxiety,apathy, cognitive difficulty, depression, fatigue, headache, insomnia,irritability, body pain, and psychosis). The term “pharmaceuticallyacceptable salt” also refers to a salt prepared by contacting an agent(e.g., anipamil, candesartan, devapamil, falipamil, gallopamil,telmisartan, tiapamil, or verapamil), where the agent has an acidicfunctional group (e.g., a carboxylic acid functional group), with apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared by contacting an agent (e.g., anipamil, candesartan, devapamil,falipamil, gallopamil, telmisartan, tiapamil, or verapamil), where theagent has a basic functional group (e.g., an amino functional group),with a pharmaceutically acceptable inorganic or organic acid. Suitableacids include, but are not limited to, hydrogen sulfate, citric acid,acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogeniodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid,salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleicacid, besylic acid, fumaric acid, gluconic acid, glucaronic acid,saccharic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

The compositions of the present invention can contain a salt ofmagnesium, optionally magnesium oxide (MgO).

Pharmaceutical Therapeutics

For therapeutic uses, compositions comprising a first agent selectedfrom one or more of anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil, and a second agent selected from one or more ofcandesartan and telmisartan can be administered systemically. Preferableroutes of administration include, for example, oral administration orsubcutaneous, intravenous, interperitoneally, intramuscular, orintradermal injections that provide continuous, sustained levels of thedrug in the patient. Treatment of human patients or other animals willbe carried out using a therapeutically effective amount (e.g., fortreatment of a panic disorder) of a therapeutic identified herein in aphysiologically-acceptable carrier. Anipamil, devapamil, falipamil,gallopamil, tiapamil, and/or verapamil in combination with candesartanand/or telmisartan can be formulated in a pharmaceutically-acceptablebuffer such as physiological saline. Suitable carriers and theirformulation are described, for example, in Remington's PharmaceuticalSciences by E. W. Martin. The amount of the therapeutic agent to beadministered varies depending upon the manner of administration, the ageand body weight of the patient, and with the clinical symptoms of abrain and/or behavioral health disorder. The clinical symptoms, in someembodiments, are the ten cardinal neuropsychiatric symptoms (i.e.,anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, pain (e.g., body pain), and psychosis).Generally, amounts will be in the range of those used for other agentsused in the treatment of a brain and/or behavioral health disorder. Insome embodiments, a composition comprising verapamil and telmisartan,verapamil and candesartan, or candesartan and/or telmisartan incombination with one or more of anipamil, devapamil, falipamil,gallopamil, tiapamil, and verapamil is administered at a dosage that iseffective at reducing one or more of the ten cardinal neuropsychiatricsymptoms (i.e., anxiety, apathy, cognitive difficulty, depression,fatigue, headache, insomnia, irritability, body pain, and psychosis.Effectiveness of the administration can be determined by a method knownto one skilled in the art, or using any assay that measures one or moreof the ten neuropsychiatric symptoms (e.g., behavioral assessment,neuropsychological testing, etc.). For example, in some presentlydisclosed embodiments, effectiveness of the treatment can be measured bypatient self-reports of symptoms and/or via NIH toolbox testing.Effectiveness can also be measured outcomes on disease-specific,gold-standard outcome measures, including measures that assess not onlysymptoms and function but also overall life satisfaction or quality oflife.

Formulation of Pharmaceutical Compositions

The administration of a composition containing a first agent selectedfrom one or more of anipamil, devapamil, falipamil, gallopamil,tiapamil, and verapamil and a second agent selected from one or more ofcandesartan and telmisartan can be administered to a subject for thetreatment of a brain and/or behavioral health disorder (e.g., panicdisorder) by any suitable means that results in a concentration of thetherapeutic that, combined with other components, is effective inameliorating, reducing, or stabilizing one or more of the ten cardinalneuropsychiatric symptoms. In some embodiments, the combination treatsone or more of the ten cardinal neuropsychiatric symptoms (i.e.,anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, body pain, and psychosis). The compositions cancontain a salt of magnesium, optionally magnesium oxide (MgO). Thecomposition can be contained in any appropriate amount any suitablecarrier substance, that is generally present in an amount of 1-95% byweight of the total weight of the composition. The composition can beprovided in a dosage form that is suitable for oral administration. Insome embodiments, the composition can be provided in a dosage form thatis suitable for a parenteral (e.g., subcutaneously, intravenously,intramuscularly, or intraperitoneally) administration route. Thepharmaceutical compositions can be formulated according to conventionalpharmaceutical practice (see, e.g., Remington: The Science and Practiceof Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams &Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J.Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Human dosage amounts can initially be determined by extrapolating fromthe amount of anipamil, candesartan, devapamil, falipamil, gallopamil,telmisartan, tiapamil, verapamil, or combinations thereof, used in mice.Dosages can also be determined based on dosages for the effectivetreatment of disorders for which the individual agents have beenindicated in humans. The dosage (optionally a daily dosage) amount ofone or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil, individually or collectively, can be from about 120 mg toabout 480 mg, from about 250 mg to about 360 mg, from about 200 mg toabout 500 mg, from about 250 mg to about 350 mg, from about 120 mg toabout 720 mg, or about 288 mg. The dosage amount of the second agent canbe from about 80 mg to about 400 mg, from about 45 mg to about 180 mg,from about 80 mg to about 320 mg, from about 45 mg to about 150 mg, fromabout 90 mg to about 200 mg, or about 96 mg. In embodiments, the dosageamount of the second agent is greater than 70 mg, 75 mg, 80 mg, 85 mg,90 mg, 95 mg, 100 mg, or 150 mg. The dosage of the first agent orcomponents thereof and the second agent or components thereof can becontained in one or multiple dosage forms.

In some embodiments, the daily dosage of either the first or the secondagent is administered more than once per day. For example, in someembodiments, the daily administration (e.g., 80 mg) is delivered in two40 mg doses twice per day.

The first agent and the second agent can be administered to a subject(optionally as a dosage form) at a dosage ratio (mass:mass) of the firstagent (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil,verapamil, or combinations thereof) to the second agent (e.g.,candesartan, telmisartan, or combinations thereof) of about or at leastabout 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. In some embodiments,the dosage ratio of the first agent (e.g., anipamil, devapamil,falipamil, gallopamil, tiapamil, verapamil, or combinations thereof) tothe second agent (e.g., candesartan, telmisartan, or combinationsthereof) is less than about 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. The firstagent (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil,verapamil, or combinations thereof) can be administered to a subject ata daily dosage that is about double or triple a daily dosage of thesecond agent (e.g., candesartan, telmisartan, or combinations thereof)administered to the subject. In some embodiments, the dosage amounts forthe first agent (e.g., anipamil, devapamil, falipamil, gallopamil,tiapamil, verapamil, or combinations thereof), the second agent (e.g.,candesartan, telmisartan, or combinations thereof), or componentsthereof (e.g., anipamil, candesartan, devapamil, falipamil, gallopamil,telmisartan, tiapamil, verapamil, or combinations thereof), individuallyor in combination, can vary from between about 0.1 mg compound/Kg bodyweight to about 2 mg compound/Kg body weight; or from about 0.5 mg/Kgbody weight to about 2 mg/Kg body weight or from about 1.0 mg/Kg bodyweight to about 2 mg/Kg body weight; or from about 1.5 mg/Kg body weightto about 2 mg/Kg body weight; or from about 0.1 mg/Kg body weight toabout 1.5 mg/Kg body weight; or from about 0.10 mg/Kg body weight toabout 1.0 mg/Kg body weight; or from about 0.10 mg/Kg body weight toabout 0.5 mg/Kg body weight. In other embodiments this dose can be about0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, or 3.0mg/Kg body weight. In other embodiments, it is envisaged that doses canbe in the range of about 0.2 mg compound/Kg body to about 2 mgcompound/Kg body. Of course, the dosage amounts can be adjusted upwardor downward, as is routinely done in such treatment protocols, dependingon the results of the initial clinical trials and the needs of aparticular patient.

The dosage amount (optionally a daily dosage) of a magnesium salt (e.g.,MgO) in embodiments is about or at least about 100 mg, 150 mg, 200 mg,250 mg, 300 mg, 350 mg, 400 mg, or 500 mg. The dosage amount (optionallya daily dosage) of a magnesium salt (e.g., MgO) in embodiments is nomore than about 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg.

Pharmaceutical compositions according to the presently disclosedembodiments can be formulated to release the active compound (e.g.,anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan,tiapamil, and verapamil, or combinations thereof) substantiallyimmediately upon administration or at any predetermined time or timeperiod after administration. The latter types of compositions aregenerally known as controlled release formulations, which include (i)formulations that create a substantially constant concentration of thedrug within the body over an extended period of time; (ii) formulationsthat after a predetermined lag time create a substantially constantconcentration of the drug within the body over an extended period oftime; (iii) formulations that sustain action during a predetermined timeperiod by maintaining a relatively, constant, effective level in thebody with concomitant minimization of undesirable side effectsassociated with fluctuations in the plasma level of the active substance(sawtooth kinetic pattern); (iv) formulations that localize action by,e.g., spatial placement of a controlled release composition nearintended targeted cells (e.g., brain cells); (v) formulations that allowfor convenient dosing, such that doses are administered, for example,orally once or twice per day; and (vi) formulations that target calciumchannels and angiotensin receptors by using carriers or chemicalderivatives to deliver the therapeutic agent to a particular cell type(e.g., brain cell). For some applications, controlled releaseformulations obviate the need for frequent dosing during the day tosustain the plasma level at a therapeutic level.

Any of a number of strategies can be pursued in order to obtaincontrolled release in which the rate of release outweighs the rate ofmetabolism of the compound in question. In one example, controlledrelease is obtained by appropriate selection of various formulationparameters and ingredients, including, e.g., various types of controlledrelease compositions and coatings. Thus, the therapeutic is formulatedwith appropriate excipients into a pharmaceutical composition that, uponadministration, releases the therapeutic in a controlled manner.Examples include single or multiple unit tablet or capsule compositions,oil solutions, suspensions, emulsions, microcapsules, microspheres,molecular complexes, nanoparticles, patches, and liposomes.

Parenteral Compositions

The pharmaceutical composition can be administered parenterally byinjection, infusion or implantation (subcutaneous, intravenous,intramuscular, intraperitoneal, or the like) in dosage forms,formulations, or via suitable delivery devices or implants containingconventional, non-toxic pharmaceutically acceptable carriers andadjuvants. The formulation and preparation of such compositions are wellknown to those skilled in the art of pharmaceutical formulation.Formulations can be found in Remington: The Science and Practice ofPharmacy, supra.

Compositions for parenteral use can be provided in unit dosage forms(e.g., in single-dose ampoules), or in vials containing several dosesand in which a suitable preservative can be added (see below). Thecomposition can be in the form of a solution, a suspension, an emulsion,an infusion device, or a delivery device for implantation, or it can bepresented as a dry powder to be reconstituted with water or anothersuitable vehicle before use. Apart from the active agent that reduces orameliorates one or more of the ten cardinal neuropsychiatric symptoms(i.e., anxiety, apathy, cognitive difficulty, depression, fatigue,headache, insomnia, irritability, body pain, and psychosis), thecomposition can include suitable parenterally acceptable carriers and/orexcipients. The active therapeutic agent(s) can be incorporated intomicrospheres, microcapsules, nanoparticles, liposomes, or the like forcontrolled release. Furthermore, the composition can include suspending,solubilizing, stabilizing, pH-adjusting agents, tonicity adjustingagents, and/or dispersing, agents.

As indicated above, the pharmaceutical compositions according to thepresently disclosed embodiments can be in the form suitable for sterileinjection. To prepare such a composition, one or more of anipamil,candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil,and verapamil is dissolved or suspended in a parenterally acceptableliquid vehicle. Among acceptable vehicles and solvents that can beemployed are water, water adjusted to a suitable pH by addition of anappropriate amount of hydrochloric acid, sodium hydroxide or a suitablebuffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloridesolution and dextrose solution. The aqueous formulation can also containone or more preservatives (e.g., methyl, ethyl or n-propylp-hydroxybenzoate). In cases where one of the compounds is onlysparingly or slightly soluble in water, a dissolution enhancing orsolubilizing agent can be added, or the solvent can include 10-60% w/wof propylene glycol or the like.

Controlled Release Parenteral Compositions

Controlled release parenteral compositions can be in form of aqueoussuspensions, microspheres, microcapsules, magnetic microspheres, oilsolutions, oil suspensions, or emulsions. Alternatively, the activedrugs can be incorporated in biocompatible carriers, liposomes,nanoparticles, implants, or infusion devices.

Materials for use in the preparation of microspheres and/ormicrocapsules are, e.g., biodegradable/bioerodible polymers such aspolygalactin, poly-(isobutyl cyanoacrylate),poly(2-hydroxyethyl-L-glutamine) and, poly(lactic acid). Biocompatiblecarriers that can be used when formulating a controlled releaseparenteral formulation are carbohydrates (e.g., dextrans), proteins(e.g., albumin), lipoproteins, or antibodies. Materials for use inimplants can be non-biodegradable (e.g., polydimethyl siloxane) orbiodegradable (e.g., poly(caprolactone), poly(lactic acid),poly(glycolic acid) or poly(ortho esters) or combinations thereof).

Solid Dosage Forms for Oral Use

Formulations for oral use include tablets containing the activeingredients (e.g., one or more of anipamil, candesartan, devapamil,falipamil, gallopamil, telmisartan, tiapamil, and verapamil) in amixture with non-toxic pharmaceutically acceptable excipients. Suchformulations are known to the skilled artisan. Excipients can be, forexample, inert diluents or fillers (e.g., sucrose, sorbitol, sugar,mannitol, microcrystalline cellulose, starches including potato starch,calcium carbonate, sodium chloride, lactose, calcium phosphate, calciumsulfate, or sodium phosphate); granulating and disintegrating agents(e.g., cellulose derivatives including microcrystalline cellulose,starches including potato starch, croscarmellose sodium, alginates, oralginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia,alginic acid, sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, and the like.

The tablets are uncoated in some embodiments and coated in otherembodiments. The tablets can be coated by known techniques, optionallyto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. The coating canbe adapted to release the active drug or drugs in a predeterminedpattern (e.g., in order to achieve a controlled release formulation) oradapted not to release the active drug until after passage of thestomach (enteric coating). The coating, in some embodiments, is a sugarcoating, a film coating (e.g., based on hydroxypropyl methylcellulose,methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/orpolyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylicacid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).Furthermore, a time delay material, such as, e.g., glyceryl monostearateor glyceryl distearate can be employed.

The solid tablet compositions include, in some embodiments, a coatingadapted to protect the composition from unwanted chemical changes,(e.g., chemical degradation prior to the release of the first and/orsecond agent). In some embodiments, the coating is applied on the soliddosage form in a similar manner as that described in Encyclopedia ofPharmaceutical Technology, supra.

One or more of anipamil, candesartan, devapamil, falipamil, gallopamil,telmisartan, tiapamil, and verapamil are mixed together in the tablet orpartitioned. In one example, a first agent (e.g. one or more ofanipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) iscontained on the inside of the tablet, and a second agent (e.g., one ormore of candesartan and telmisartan) is on the outside, such that asubstantial portion of the second agent is released prior to the releaseof the first agent. In some embodiments, the second agent (e.g., one ormore of candesartan and telmisartan) is contained on the inside of thetablet and the first agent (e.g. one or more of anipamil, devapamil,falipamil, gallopamil, tiapamil, and verapamil) is on the outside.

Formulations for oral use include chewable tablets or hard gelatincapsules, wherein the active ingredients (i.e., anipamil, candesartan,devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil,or combinations thereof) are mixed with an inert solid diluent (e.g.,potato starch, lactose, microcrystalline cellulose, calcium carbonate,calcium phosphate, or kaolin), or as soft gelatin capsules, wherein theactive ingredients are mixed with water or an oil medium, for example,peanut oil, liquid paraffin, or olive oil. Powders and granulates areprepared in some embodiments using the ingredients mentioned above undertablets and capsules in a conventional manner using, e.g., a mixer, afluid bed apparatus, or a spray drying equipment.

Controlled Release Oral Dosage Forms

Controlled release compositions of a first agent selected from one ormore of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil and a second agent that is selected from one or more ofcandesartan and telmisartan (e.g., for oral use) can be constructed torelease the agents by controlling the dissolution and/or the diffusionof the active substance. For example, an immediate release formulationis commercially available for verapamil and telmisartan, as are extendedrelease versions of verapamil. The verapamil extended release (ER)formulations release the drug over 12 or 24 hours. Dissolution ordiffusion-controlled release can be achieved by appropriate coating of atablet, capsule, pellet, or granulate formulation of compounds, or byincorporating a composition comprising the first and/or second agentsinto an appropriate matrix or matrices. A controlled release coatingincludes, in some embodiments, one or more of the coating substancesmentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax,carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryldistearate, glycerol palmitostearate, ethylcellulose, acrylic resins,dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride,polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate,methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3butylene glycol, ethylene glycol methacrylate, and/or polyethyleneglycols. In a controlled release matrix formulation, the matrix materialcan also include, e.g., hydrated metylcellulose, carnauba wax andstearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

A controlled release composition containing two agents described herein(e.g., one or more of verapamil, anipamil, devapamil, falipamil,gallopamil, and tiapamil and one or more of telmisartan and candesartan)is, in some embodiments, in the form of a buoyant tablet or capsule(i.e., a tablet or capsule that, upon oral administration, floats on topof the gastric content for a certain period of time). A buoyant tabletformulation of the composition can be prepared by granulating a mixtureof one or more of the agents, or components thereof, with excipients and20-75% w/w of hydrocolloids, such as hydroxyethylcellulose,hydroxypropylcellulose, or hydroxypropylmethylcellulose. The obtainedgranules can then be compressed into tablets. On contact with thegastric juice, the tablet forms a substantially water-impermeable gelbarrier around its surface. This gel barrier takes part in maintaining adensity of less than one, thereby allowing the tablet to remain buoyantin the gastric juice.

The presently disclosed embodiments provide methods of treating one ormore of the ten cardinal neuropsychiatric symptoms (i.e., anxiety,apathy, cognitive difficulty, depression, fatigue, headache, insomnia,irritability, body pain, and psychosis) that comprise administering atherapeutically effective amount of a pharmaceutical composition(s)comprising the first agent (e.g., one or more of anipamil, devapamil,falipamil, gallopamil, tiapamil, and verapamil) and the second agent(e.g., one or more of candesartan and telmisartan) to a subject (e.g., amammal such as a human). Thus, one embodiment is a method of treating asubject suffering from or susceptible to a disease or disorder thatcauses one or more of the ten cardinal neuropsychiatric symptoms (i.e.,anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, body pain, and psychosis). The method includesthe step of administering to the subject a therapeutic amount of acombination of the first agent and the second agent sufficient to treatthe disease, condition, disorder or symptom thereof, under conditionssuch that the disease, condition, disorder or symptom thereof istreated. The therapeutic methods include prophylactic treatment. In someembodiments, the subject is a mammal, particularly a human sufferingfrom, having, susceptible to, or at risk for disease or disorder thatcauses one or more of the ten cardinal neuropsychiatric symptoms (i.e.,anxiety, apathy, cognitive difficulty, depression, fatigue, headache,insomnia, irritability, body pain, and psychosis).

Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

Combination Therapies

Optionally, the first agent (e.g., one or more of anipamil, devapamil,falipamil, gallopamil, tiapamil, and verapamil) and/or the second agent(e.g., one or more of candesartan and telmisartan), can be administeredtogether with any other standard anti-anxiety, anti-migraine,anti-depression, anti-cognitive difficulty, anti-anger, anti-apathy,anti-fatigue, anti-pain, anti-psychosis, or anti-insomnia therapy suchas cognitive behavioral therapy, sedatives, etc.; such methods are knownto the skilled artisan and described in Remington's PharmaceuticalSciences by E. W. Martin. If desired, the first agent (e.g., one or moreof anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil)and/or the second agent (e.g., one or more of candesartan andtelmisartan) is administered in combination with any conventionalanti-anxiety therapy, including but not limited to, anxiolytic and/orsedative drugs, antipsychotics, mood stabilizers, anticonvulsants,antihistamines, and antidepressants.

The compositions of the present invention can be administered to asubject to treat a neuropsychological condition. The neuropsychologicalcondition can be a brain and/or behavioral disorder. Non-limitingexamples of brain and behavioral health disorders include affectivedisorders, anxiety disorders, neurodegenerative disorders,neurodevelopmental disorders, psychotic disorders, personalitydisorders, migraine disorders and somatoform disorders. Examples ofaffective disorders include bipolar disorder, cyclothymia, depression,dysthemia, generalized anxiety disorder, major depressive disorder,obsessive compulsive disorder, postpartum depression, post-traumaticstress disorder (PTSD), phobias, and seasonal affective disorder.Examples of anxiety disorders include panic disorder, social anxietydisorder, post-traumatic stress disorder, obsessive compulsive disorderand specific phobia. Examples of neurodegenerative disorders includeAlzheimer's disease and Parkinson's disease. Examples ofneurodevelopmental disorders include autism spectrum disorder, attentiondeficit hyperactive disorder (ADHD) and learning disorders. Examples ofpsychotic disorders include schizophrenia, schizoaffective disorder andmajor depression with psychosis. Examples of personality disordersinclude paranoid, schizoid, schizotypal, antisocial, borderline,histrionic, narcissistic, avoidant, dependent and obsessive-compulsivepersonality disorder. Examples of migraine-related disorders includemigraine with aura, migraine without aura, acephalgic migraine, andbasilar migraine. Examples of somatoform disorders include somatizationdisorder, hypochondriasis, conversion disorder, body dysmorphic disorderand chronic pain. The symptoms associated with the disease can beselected from one or more of the “ten cardinal symptoms” associated withbrain and behavioral health disorders: anxiety, apathy, cognitivedifficulty, depression, fatigue, headache, insomnia, irritability, bodypain, and psychosis. Administration of a composition or dosage form ofthe present invention to a subject can reduce or ameliorate one or moreof the symptoms associated with the bran and/or behavioral disorder.

The compositions of the present invention can be administered to asubject in an amount sufficient to alter regional cerebral blood flow inthe subject. The cerebral regions can include one or more of thetelencephalon, the diencephalon, and the mesencephalon. The compositionsof the present invention can be administered to the subject in an amountsufficient to result in hemodynamic equilibrium in functional brainnetworks that coordinate among regions within the telencephalon, thediencephalon, and the mesencephalon in a subject.

Selection of Patients for Treatment

The present disclosure provides for the selection of patients who arelikely to benefit from treatment with a therapeutic combinationdescribed herein. Such patients are selected as having a brain orbehavior health disorders or a symptom thereof (e.g., anxiety, apathy,cognitive difficulty, depression, fatigue, headache, insomnia,irritability, body pain, and psychosis). Patients having a brain orbehavior health disorders or a symptom thereof are selected for therapywith a combination therapeutic comprising a first agent selected fromone or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil and a second agent that is one or more of candesartan andtelmisartan.

Not being bound by theory, patients with the greatest energysupply/demand mismatch can have the greatest benefit from thecompositions of the present disclosure. Patients with energysupply/demand mismatch can show the largest changes in functionalconnectivity before and after combination treatment. Four energydemand/supply phenotypes emerge when one considers energy as binary(high vs. low). The four types are: high demand/high supply (low risk ofneuropsychiatric symptomatology), high demand/low supply (high risk ofneuropsychiatric symptomatology), low demand/high supply (low risk ofneuropsychiatric symptomatology), and low demand/low supply (low risk ofneuropsychiatric symptomatology).Kits or Pharmaceutical Systems

The present compositions can be assembled into kits or pharmaceuticalsystems for treating a brain or behavior health disorder or a symptomthereof (e.g., anxiety, migraine, depression, cognitive difficulty,anger, apathy, fatigue, pain, psychosis, or insomnia). Kits orpharmaceutical systems comprise a carrier means, such as a box, carton,tube or the like, having in close confinement therein one or morecontainer means, such as vials, tubes, ampoules, bottles and the like.The kits or pharmaceutical systems can also comprise associatedinstructions for using the agents of the presently disclosedembodiments. In some embodiments, kits include the first agent (e.g.,one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, andverapamil) and the second agent (e.g., one or more of candesartan andtelmisartan).

The practice of the presently disclosed embodiments employs, unlessotherwise indicated, conventional techniques of molecular biology(including recombinant techniques), microbiology, cell biology,biochemistry and immunology, which are well within the purview of theskilled artisan. Such techniques are explained fully in the literature,such as, “Molecular Cloning: A Laboratory Manual”, second edition(Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal CellCulture” (Freshney, 1987); “Methods in Enzymology” “Handbook ofExperimental Immunology” (Weir, 1996); “Gene Transfer Vectors forMammalian Cells” (Miller and Calos, 1987); “Current Protocols inMolecular Biology” (Ausubel, 1987); “PCR: The Polymerase ChainReaction”, (Mullis, 1994); “Current Protocols in Immunology” (Coligan,1991). These techniques are applicable to the production of thepolynucleotides and polypeptides of the invention, and, as such, can beconsidered in making and practicing the invention. Particularly usefultechniques for particular embodiments will be discussed in the sectionsthat follow.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the assay, screening, and therapeutic methods of theinvention, and are not intended to limit the scope of what the inventorsregard as their invention.

EXAMPLES Example 1: Novel Clinical Effects of Combination Treatment withVerapamil and Telmisartan—A Retrospective, Observational Cohort Study

A study was completed to measure the novel clinical effects ofcompositions containing verapamil and telmisartan for treatment ofneuropsychiatric symptomatologies in adults. The specific aims of thisstudy were to describe 1) the magnitude of novel clinical effects onsymptomatology; 2) the magnitude of novel clinical effects onpsychosocial outcomes; and 3) the unique clinical effects that resultfrom combination but not monotherapy treatment. For the main analysis,results were compared On vs. Off treatment across all patients.

Symptomatology On vs. Off Combination Treatment

Patients receiving combination treatment versus no treatment showeddrastic reductions in overall symptomatology as measured by the sum ofthe ten cardinal disabling symptoms (i.e., anxiety, apathy, cognitivedifficulty, depression, fatigue, headache, insomnia, irritability, bodypain, and psychosis) and in 9/10 of the individual symptoms, includinganxiety, depression, irritability, apathy, fatigue, body pain, insomnia,headache, and cognitive difficulty. All p-values were less than 0.001.All effect sizes were medium to large except effect sizes for depressionand insomnia and headache which were small. Some effect sizes, includingthose for overall symptomatology, anxiety and apathy, were significantlylarge (above 1.0) (FIGS. 1A-1J).

Standardized Psychosocial Outcomes On and Off Treatment

Patients receiving combination treatment versus no treatment showedsignificant improvements in 6/10 of the standardized measures ofpsychosocial health, including General Life Satisfaction, Meaning &Purpose, Emotional Support, Instrumental Support, Friendship andLoneliness. All p-values were less than 0.1. All effect sizes weremedium to large except for Meaning & Purpose (FIGS. 2A-2F).

Uniqueness of Combination Treatment vs. Individual Monotherapies

Outcomes from combination therapy were significantly different fromoutcomes from monotherapy with either telmisartan alone or withverapamil twice daily alone. Compared to the telmisartan only group,patients receiving combination treatment showed significantly improvedoutcome scores in NIH Toolbox measures of General Life Satisfaction(p<0.01) and Anger [Hostility] (p<0.04) (FIGS. 3A-3B).

Compared to the verapamil group, patients receiving combinationtreatment showed significantly different scores in NIH Toolbox measuresof NIH Toolbox Self-Efficacy (p<0.05) and Anger [Aggression] (p<0.06)(FIGS. 4A-4B).

Example 2: An Observational Cohort Study of Compositions ContainingVerapamil and Telmisartan, a Novel Combination Treatment forNeuropsychiatric Symptomatology in Adults

An observational cohort study was completed to evaluate the safety andefficacy of compositions containing verapamil and telmisartan fortreatment of neuropsychiatric symptomatologies in adults. The specificaims of this study were to 1) measure the safety of combinationtreatment, 2) compare efficacy of combination treatment across differentsymptoms and for patients with different disorders; and 3) use aphysiological measure (the Weber test) to test whether the mechanism ofaction of the combination of treatment results in the normalization offunctional connectivity in the auditory functional network. For the mainanalysis, results were compared before and after treatment in the samepatient.

Demographics

A total of 102 patients received combination therapy and consented tothe CEDAR study (Protocol Number: CEDAR2017 originally approved byAspire IRB on Apr. 11, 2017). Demographic details as well as informationon handedness, primary diagnosis, pre-existing medications, and presenceof cardiovascular diagnosis can be found in Table 2.

TABLE 2 Baseline Demographics Baseline Characteristic (n = 102) Age (SD)46.0% (14.0) Gender Male 57.8% (59) Female 42.2% (43) Race White orCaucasian 82.4% (84) African or black 15.7% (16) Asian 1.0% (1) Mixed1.0% (1) Education Less than High School 11.1% (11) High School, GED, orequivalent 23.2% (23) Associate's or some college 36.4% (36) Bachelor's18.2% (18) Master's and above 11.2% (11) Handedness Right 71.1% (69)Left 7.2% (2) Ambidextrous 21.7% (21) Primary Diagnosis Panic Disorder19.6% (20) PTSD 11.8% (12) Chronic Pain syndrome 5.9% (6) Other 63.5%(64) Pre-existing medications Anti-depressants 40.3% (31)Benzodiazepines 37.7% (29) Stimulants 18.2% (14) Opiates 39.2% (29)Anti-psychotics 15.6% (12) Mood stabilizers 18.2% (14) PriorCardiovascular Diagnosis 33.7% (35)Self-Report Neuropsychiatric Symptomatology

Patients receiving combination treatment showed significant reductionsin symptomatology across eight out of 10 of the cardinal disablingsymptoms (other than fatigue and psychosis); the greatest effects wereseen for apathy, anxiety, cognitive difficulty and overallneuropsychiatric disability (see Table 3).

In patients with high anxiety at baseline (7 or above), patientsreceiving combination treatment showed significant reductions insymptomatology across nine out of 10 of the cardinal disabling symptoms.Effect sizes were large for anxiety, irritability, apathy and overallneuropsychiatric disability, medium for depression, insomnia, andcognitive difficulty and small for all remaining symptoms (fatigue, painand headache) (see Table 4). In patients with moderate anxiety atbaseline (4 or above), effect sizes were medium for anxiety, apathy,cognitive disturbance and overall neuropsychiatric disability and smallfor all remaining symptoms besides psychosis (see Table 5).

In patients with high baseline cognitive difficulty (7 or above), effectsizes were large for apathy, cognitive difficulty and overallneuropsychiatric disability, medium for anxiety, depression, andirritability, and small for anxiety, body pain and insomnia (see Table6). In patients with moderate baseline cognitive difficulty (4 orabove), effect sizes were large for cognitive difficulty, medium foranxiety, depression, irritability, apathy and overall neuropsychiatricdisability, and small for fatigue and insomnia (See Table 7).

TABLE 3 Effect of Combination Treatment on Self-ReportedNeuropsychiatric Symptomatology (Last observation mean follow-up was 8.9months) Baseline First Baseline Last (n =77) Observation P-value Cohen's(n = 61) Observation P-value Cohen's Anxiety 5.6 4.5 0.0020* 0.39 5.44.1 0.0017* 4.44 Depression 4.7 4.1 0.1007 0.19 4.6 3.6 0.0328* 0.28Irritability 4.4 3.6 0.0563 0.25 4.2 3.4 0.0481* 0.27 Apathy 4.8 3.30.0002* 0.49 4.6 3.1 0.0017* 0.47 Fatigue 4.6 4.0 0.1004 0.19 4.4 3.90.1080 0.19 Body pain 4.8 4.2 0.1523 0.08 5.0 4.1 0.0103* 0.29 Insomnia4.5 3.8 0.0703 0.21 4.4 3.4 0.0257 0.31 Headache 3.0 2.5 0.1178 0.16 3.12.2 0.4091* 0.29 Psychosis 0.9 0.9 0.9563 −0.01 0.9 0.8 0.5942 0.05Cognitive 5.1 3.9 0.0023* 0.37 4.9 3.7 0.0032* 0.41 DisabilityNeuropsychiatric 42.4 34.6 0.0033* 0.34 41.6 32.2 0.0008* 0.41Disability

TABLE 4 Self-report Symptomatology in Patients with Baseline SevereAnxiety Before and After Combination Treatment Baseline First (n = 34)Observation P-value Cohen's Anxiety 8.1 5.1 0.0000* 1.24 Depression 6.64.7 0.0031* 0.54 Irritability 6.7 4.4 0.0015* 0.75 Apathy 6.2 3.90.0002* 0.71 Fatigue 6.0 4.7 0.0283* 0.41 Body pain 5.8 4.8 0.0204* 0.27Insomnia 6.4 4.6 0.0031* 0.56 Headache 4.0 2.6 0.0298* 0.44 Psychosis1.5 1.3 0.7103  0.06 Cognitive Disability 6.4 4.5 0.0009* 0.59Neuropsychiatric Disability 57.8 40.4 0.0000* 0.74

TABLE 5 Self-report Symptomatology in Patients with Baseline ModerateAnxiety Before and After Combination Treatment Baseline First (n = 60)Observation P-value Cohen's Anxiety 6.8 5.1 0.0001* 0.67 Depression 5.84.6 0.0124* 0.36 Irritability 5.4 4.1 0.0127* 0.41 Apathy 5.5 3.60.0000* 0.64 Fatigue 5.5 4.5 0.0267* 0.33 Body pain 5.5 4.6 0.0495* 0.25Insomnia 5.4 4.3 0.0276* 0.30 Headache 3.4 2.4 0.0274* 0.30 Psychosis1.1 1.0 0.7403  0.04 Cognitive Disability 5.8 4.2 0.0005* 0.51Neuropsychiatric Disability 50.0 38.4 0.0001* 0.56

TABLE 6 Self-report Symptomatology in Patients with Baseline SevereCognitive Disturbance Before and After Combination Treatment BaselineFirst (n = 32) Observation P-value Cohen's Anxiety 6.9 5.8 0.0348* 0.42Depression 6.8 5.0 0.0041* 0.62 Irritability 6.2 4.5 0.0142* 0.54 Apathy6.4 3.7 0.0000* 0.93 Fatigue 6.1 5.2 0.1311  0.36 Body pain 6.5 5.20.0423* 0.40 Insomnia 6.4 5.0 0.0206* 0.42 Headache 3.6 3.4 0.7878  0.06Psychosis 1.3 1.4 0.8933  0.02 Cognitive Disability 8.3 5.3 0.0000* 1.26Neuropsychiatric Disability 58.6 44.5 0.0015* 0.71

TABLE 7 Self-report Symptomatology in Patients with Baseline ModerateCognitive Disturbance Before and After Combination Treatment BaselineFirst (n = 51) Observation P-value Cohen's Anxiety 6.4 5.0 0.0019* 0.50Depression 6.0 4.4 0.0014* 0.49 Irritability 5.7 4.1 0.0027* 0.50 Apathy5.5 3.6 0.0005* 0.61 Fatigue 5.5 4.5 0.0407* 0.34 Body pain 5.9 4.90.0683  0.29 Insomnia 5.5 4.1 0.0111* 0.36 Headache 3.6 2.7 0.1090  0.30Psychosis 1.3 1.1 0.6420  0.06 Cognitive Disability 7.0 4.5 0.0000* 0.90Neuropsychiatric Disability 52.3 39.1 0.0001* 0.62NIH Toolbox Standardized Outcome Measures

NIH Toolbox measurements showed significant improvements in general lifesatisfaction and borderline significant improvements in socialsatisfaction (Table 8). Outcomes with smaller sample sizes includingprocessing speed (n=17) and dimensional change card sort (n=18) showedno significant changes before and after treatment (see Table 8).

TABLE 8 NIH Toolbox Standardized Outcome Measures First BaselineObservation P-value Cohen's Processing Speed (n = 18) 39.3 49.7 0.81700.16 Dimensional Change 54.2 56.9 0.3550 0.19 Card (n = 17) General Life37.6 41.5  0.0212* 0.34 Satisfaction (n = 41) Meaning and Purpose (n =42) 39.4 41.3 0.1743 0.19 Social Satisfaction (n = 41) 35.6 38.1 0.09410.22Weber Lateralization Showing Bi-directional Changes of Observations ofSensorineural Function

The Weber test is a common clinical examination technique that aphysician can use to identify sensorineural hearing loss. The Weber testemploys a tuning fork, which is placed in the center of the upperforehead, with a prompt asking the patient to report whether the soundlateralizes to the left or to the right. In a patient with sensorineuralhearing loss, the sound lateralizes to the stronger side. Patients withneuropsychiatric disorders (e.g., brain and/or behavioral healthdisorders) without sensorineural hearing loss frequently reportlateralization to the left or right when tested with the Weber test.This lateralization could be due to the fact that, in fact, auditoryfunctional networks can be left-, right- or bilaterally dominant(Asymmetries of the planum temporale and Heschl's gyrus: relationship tolanguage lateralization. Dorsaint-Pierre R, Penhune V B, Watkins K E,Neelin P, Lerch J P, Bouffard M, Zatorre R J. Brain. 2006 May; 129(Pt5):1164-76. doi: 10.1093/brain/aw1055. Epub 2006 Mar. 14).

FIG. 7 shows changes in Weber lateralization in patients who eitherstarted, stopped or changed dose of a composition containing verapamiland telmisartan. These changes were not present at visit intervalsduring which the composition dose remained stable. Remarkably, in somepatients, the Weber result corrected towards the left while, in otherpatients, the Weber result corrected towards the right.

For a total of 23 patients, Weber test results were available bothbefore and after treatment (see Table 9). 15 out of 18 patients who hada treatment change showed a lateralization change, whereby only one outof five patients who had no treatment change showed a lateralizationchange. This difference was statistically significant (p<0.006).

TABLE 9 Weber lateralization in patients On vs. Off CombinationTreatment .tab Latchange Txchange, chi2 Tx change Lat change no yesTotal no 4 3 7 yes 1 15 16 Total 5 18 23 Pearson chi2(1) = 7.4134 Pr =0.006Bidirectional Changes in Blood Pressure

In patients with high blood pressure at baseline, administration of thecomposition containing verapamil and telmisartan was associated withdecreases to normal levels. In patients with low blood pressure atbaseline, administration was associated with increases to normal levels.In patients with normal blood pressure at baseline, treatment was notassociated with any significant changes. The bi-directional changessuggest regulation of functional connectivity in mesencephalic brainregions that mediate autonomic balance. (FIG. 8)

Significant Differences in Social Outcomes in Patients on CombinationVs. Monotherapy

Chi-squared analysis was performed to compare the proportions ofpatients on combination therapy who reported significant social changesvs. patients on monotherapy (Table 10). At each visit, patients weresystematically assessed with self-report questions that addressed basichuman needs related to Love & Belonging. Results showed that patientswith combination therapy were significantly more likely to reportchanges in social momentum, new social contacts, dress, and appearance.Without being bound by theory, these social changes result from changesin functional brain networks related to social cognition that relyheavily on brain regions within the diencephalon and telencephalon.

TABLE 10 Comparison of the proportions of patients on combinationtherapy who reported significant social changes vs. patients onmonotherapy. P-value (Combination Therapy vs. Outcome Measure NMonotherapy)* Level 3: Love & Belonging I have momentum with respect tomy social life. 21 0.019 I have been dressing more or less formally. 350.017 I have been dressing with more or less color. 35 0.006 Since mylast visit, I cut or colored my hair. 29 0.036 Since my last visit, I'vebeen meeting new people. 21 0.038 *Monotherapy refers to telmisartanonly or verapamil onlyDiscussion

A clinical study was completed in humans using a combination ofverapamil with telmisartan to treat neuropsychiatric indications (e.g.,brain and/or behavioral health disorders). This observational study wasmotivated by clinical impressions of remarkable symptomatic improvementin patients with several common neuropsychiatric co-morbidities who weretreated serendipitously with combination therapy for approximately oneyear as part of real-world care to achieve more complete relief. Thestudy was designed to empirically test, within the limits of anobservational study design, the safety and effectiveness of combinationtreatment when delivered in the context of routine neuropsychiatriccare. Most patients received combination treatment augmented to standardof care therapies.

In 102 patients, neither systolic nor diastolic blood pressure wassignificantly different after combination treatment, despite significantimprovements in apathy, anxiety, cognitive difficulty and overallneuropsychiatric disability (e.g., a brain and/or behavioral healthdisability). Rates of adverse medical symptomatology did not changesignificantly before and after treatment. The adverse symptom profile ofcombination treatment resembled the established adverse symptom profilesof telmisartan and verapamil. Standardized testing, before and after,showed significant improvements in General Life Satisfaction.

Observational studies can provide similar estimates of effect sizes ascompared to randomized, controlled trials (Development and reliabilitytesting of a cross-cutting symptom assessment for DSM-5. AmericanJournal of Psychiatry, 170(1), 59-70. Narrow, W. E., Clarke, D. E.,Kuramoto, S. J., Kraemer, H. C., Kupfer, D. J., Greiner, L., & Regier,D. A. (2013). DSM-5 field trials in the United States and Canada, PartIII). This study includes several strengths that support the accuracy ofeffect sizes noted. These include the large sample size, thelongitudinal study design allowing for analysis of temporal effects, thelong duration of follow-up, the inclusion of patients with multipleco-morbidities (which more accurately resembles real-world care), theinclusion of objective measures such as vital signs, and NIH Toolboxmeasures. Another strength of the study was the number of differentanalyses performed to test association vs. causation as per BradfordHill Criteria. In order for a factor to be considered causative vs.associative, the following criteria should be observed: strength,consistency, specificity, temporality, biological gradient,plausibility, coherence, experiment, analogy and reversibility.

Not wishing to be bound by theory, combination treatment is acting oncentral pathways that are common to more than one neuropsychiatricdisorder (e.g., a brain and/or behavioral health disorder). Withoutintending to be bound by theory, the unique combination of angiotensinII receptor blockade with concomitant adrenergic blockade leads to morebalanced distribution in cerebral blood flow particularly in thediencephalon, which is the region of the brain important for social andemotional awareness. In other words, by influencing cognition(telencephalon) simultaneously with emotion (mesencephalon), thissynergy can result in improved social cognition (diencephalon). Thishypothesis is based on findings of conspicuous social changes inpatients who took combination therapy. For example, changes wereobserved in social and dressing behavior in patients taking combinationtreatment. The results of the study showed an improvement in socialsatisfaction in patients on combination treatment. This is furthersupported by analyses of results from the Weber test, performed as partof routine visits, which measures lateralization of the brain's auditoryfunctional network. In the clinic, patients who initiated combinationtreatment or changed from monotherapy to combination treatment displayedshifts from one visit to the next in lateralization of the Weber test.Shifts in lateralization of the Weber test do not occur with standard ofcare medications.

Not wishing to be bound by theory, the composition containing verapamiland telmisartan can serve a regulatory function in brain regionsassociated with the auditory functional network. Since these changes inauditory function correlated with clinical improvements in socialfunction, the composition can affect not only auditory function, butalso the interoceptive/exteroceptive awareness as well as the socialcommunication that rely on auditory functioning. In fact, the auditorycortex participates directly in networks for emotional processing(disability and poor quality of life associated with comorbid anxietydisorders and physical conditions. Sareen J, Jacobi F, Cox B J, Belik SL, Clara I, Stein M B. Arch Intern Med. 2006 Oct. 23; 166(19):2109-16.doi: 10.1001/archinte.166.19.2109).

Methods of the Examples

The following methods were used in Example 1.

Data and Combination Therapy

Data for this study was selected from the Comparative EffectivenessDementia and Alzheimer's Registry (CEDAR) Project. The CEDAR Project isan IRB-approved, observational study of real-world care for patientsseeking treatment for any neurological, psychological or psychiatriccondition at a community-based neuropsychiatry specialty practice inBroward County, Fla. Patients received their usual course of care, whichincluded medication adjustment and routine cognitive behavioral therapyfor neurological, psychiatric and psychological co-morbidities.Treatment was not altered as a result of participation in theobservational study. Only patients who consented to the CEDAR projectwere included in this study.

The combination therapy comprised administering either 120 mg or 180 mgof verapamil twice per day and either 40 mg or 80 mg of Telmisartantwice per day. Control groups used for comparison received no amount ofeither of verapamil and telmisartan, or only telmisartan, or onlyverapamil.

Demographics

Data from a total of 76 patients who consented to the ComparativeEffectiveness Dementia and Alzheimer's Registry (CEDAR) study wasanalyzed. Average age, gender, ethnicity and education from eachtreatment group is provided in Table 11.

TABLE 11 Education Some middle Biological Gender and/or Some Not highelementary Age Reported Male Gender Not Reported school school Somecollege Master's Degree JD Mean Count Count Count Count Count CountCount Count Count Treatment Group Neither 43.26 2 80 50 0 29 1 39 8 3Telmisartan only 45.80 0 72 23 0 2 0 56 6 0 Verapamil only 41.37 6 39 250 10 2 14 11 2 telmisartan once daily and 46.52 0 19 10 0 2 0 14 0 0verapamil once daily telemisartan twice daily 46.83 0 103 83 0 17 0 8312 3 and verapamil twice daily Comparisons of Column Proportions^(c)Education Biological Gender Some middle Some Not Not and/or highelementary High school Reported Male Gender Reported school school Somecollege Master's Degree JD graduate (A) (B) (C) (A) (B) (C) (D) (E) (F)(G) Treatment Group Neither —^(a,b) D(.000) D(.019) I(.004) Telmisartanonly —^(a) C(.002) .^(a,b) .^(a) B(.001) .^(a) G(.001) Verapamil onlyB(.000) .^(a,b) D(.004) D(.001) D(.023) C(.000) I(.033) I(.044)telmisartan once daily and .^(a) .^(a,b) .^(a) .^(a) .^(a) verapamilonce daily telemisartan twice daily .^(a) B(0.17) .^(a,b) .^(a) andverapamil twice daily Ethnicity Race Not High school GED or Bachelor'sAssociate White or African or Hispanic Hispanic graduate equivalentDegree degree Not Reported Caucasian Black Asian Mixed Not Reported orLatino or Latino Count Count Count Count Count Count Count Count CountCount Count Count Treatment Group Neither 24 3 21 2 2 90 33 4 3 11 10714 Telmisartan only 2 0 26 3 0 67 28 0 0 17 56 22 Verapamil only 13 1 92 6 41 21 0 2 13 50 7 telmisartan once daily and 4 0 8 1 0 21 8 0 0 1 226 verapamil once daily telemisartan twice daily 16 4 43 8 0 142 39 2 330 134 22 and verapamil twice daily Race Ethnicity GED or Bachelor'sAssociate Not White or African or Not Not Hispanic Hispanic equivalentDegree degree Reported Caucasian Black Asian Mixed Reported or Latino orLatino (H) (I) (J) (A) (B) (C) (D) (E) (A) (B) (C) Treatment GroupNeither A(.048) Telmisartan only .^(a) B(.008) .^(a) .^(a) .^(a) B(.004)G(.009) Verapamil only B(.000) .^(a) C(.000) telmisartan once daily and.^(a) .^(a) .^(a) .^(a) verapamil once daily telemisartan twice daily.^(a) and verapamil twice daily Results are based on two-sided tests.For each significant pair, the key of the category with the smallercolumn proportion appears in the category with the larger columnproportion. Significance level for upper case letters (A, B, C): .05^(a)This category is not used in comparisons because its columnproportion is equal to zero or one. ^(b)This category is not used incomparisons because the sum of case weights is less than two. ^(c)Testsare adjusted for all pairwise comparisons within a row of each innermostsub-table using the Bonferroni correction.Diagnosis and Medical Complexity

Clinical diagnoses were made by a neurologist with behavioral neurologyfellowship training using independent medical record review completeneurological history and exam, a self-reported psychosocial assessmentadapted for the neuropsychiatry population based on Maslow's hierarchyof needs, and DSM-V Psychiatric diagnostic interview. Medical complexitywas scaled using a composite score that summarized positive affirmations(one point each) to a series of questions about prior medical, surgeryand family history.

Symptomatology and Disability

The National Institute of Health (NIH) Toolbox was used to collectprimary outcomes in cognitive, emotional and psychosocial domains. Thesemeasures were chosen because they were designed specifically to providevalid, longitudinal assessment of neuropsychiatric symptoms incommunity-based populations for children, adults, and elderly.

The primary outcomes included standardized and self-report measures ofpatients while on and off treatment. The NIH Toolbox Pattern ComparisonProcessing Speed and Dimensional Change Card Sort test fully adjustedT-scores were the primary cognitive outcomes. The NIH Toolbox NegativeAffect Composite Score and the NIH Toolbox Psychological Well-BeingComposite Score were the primary emotional and psychosocial outcomes.The Negative Affect Composite Score measures individual components offear, anger and sadness. The Psychological Well-Being Composite Scoremeasures individual components of positive affect, general lifesatisfaction, meaning & purpose, perceived stress, self-efficacy,emotional support, instrumental support, loneliness, hostility,perceived rejection and perceived hostility. To measure self-reportsymptom severity, a scale of average symptom severity across all tencardinal symptoms (i.e., anxiety, apathy, cognitive difficulty,depression, fatigue, headache, insomnia, irritability, pain (e.g., bodypain), and psychosis), individually measured from 0 to 10, andcollectively summarized from 0 through 100 scale, difficulty on a scaleof 0 through 10 as reported by the patient over the course of clinicalcare was also used as a primary outcome.

Exploratory outcomes measured psychosocial advancement including changesin social support, social behavior, relationships, career standing, andhousing status, were measured by self-report, using the total number ofself-reported positive versus negative psychosocial events over thecourse of treatment.

The medical safety of the treatment was assessed via measurement ofmedical symptomatology, as assessed by a self-report scale of the totalnumber of positively reported symptoms before and after treatment usinga patient self-report to a review of systems battery, which asksspecifically about each body system one at a time and is administered ateach visit as part of routine care. Blood pressure and pulse andmedication adherence data were collected from clinical assessmentsperformed as part of routine care.

Statistics

To measure the overall effect of combination treatment on and offtreatment, a within-group comparison of means was performed for patientsin the following treatment groups: No treatment, monotherapy (verapamilonly or telmisartan only), and combination therapy (verapamil plustelmisartan). Since the data consists of multiple, repeated visitswhereby patients were either on or off therapy with one or the othermedication, an average of all visits off of medication was used tomeasure “Off Treatment” outcomes for patients. An average of all visitson medication was used to measure “On Treatment” outcomes. Effect sizeswere calculated using Cohen's methodology and quantified using standardranges signifying small (0.2 to 0.5), medium (0.5 to 0.8) or large(above 0.8) effects of treatment.

To measure the specific effect of individual components of thecombination treatment versus the combination treatment, a between-grouppost-hoc analysis of variance was performed for patients in thefollowing treatment groups: No treatment, treatment with verapamil only,treatment with telmisartan only, and treatment with combination therapy(verapamil plus telmisartan).

The following methods were used in Example 2.

Patient Population

Data for this study was selected from the neuro well FREE Not for ProfitCorporation's Comparative Effectiveness Dementia & Alzheimer's Registry(CEDAR) Project. The CEDAR Project is an IRB-approved, observationalstudy of real-world care for patients seeking treatment for anyNeurological, Psychological or Psychiatric condition at acommunity-based Neuropsychiatry specialty practice in Broward County,Fla. The practice accepts all major health insurances and accepts peopleof all ages and all diagnoses. Patients received their usual course ofcare, which included medication adjustment and routine cognitivebehavioral therapy for neurological, psychiatric and psychologicalco-morbidities. Treatment was not altered as a result of participationin the observational study. Only patients who consented to the CEDARproject were included in this study.

Demographics & Diagnoses

Demographic details, medical history, and exam were collected at theinitial visit as part of a comprehensive initial neuropsychiatricevaluation. A comprehensive psychosocial assessment modeled afterMaslow's Hierarchy of Needs was delivered to all patients at baseline. Aclinical diagnosis was made by a neurologist with Behavioral Neurologyfellowship training using a DSM-V based Psychiatric diagnosticinterview.

Safety

Vital signs were measured using systolic, diastolic blood pressure andpulse measurements that were collected as part of routine care. Adverseevents were measured using a ten-point review of systems inventorycovering Constitutional, HEENT, Respiratory, Gastrointestinal,Genitourinary, Dermatology, Musculoskeletal, Endocrine, Neurology, andPsychiatry symptoms. A point of 1 was given for each symptom reported aspresent, for a total possible score of 93.

To calculate the rate of adverse events on combination therapy, thepercentage of people who responded “Yes” to one of the symptoms at thefirst month of treatment was calculated for each of the symptoms.

Effectiveness

Symptom severity was measured via a self-report symptom severity scalethat was delivered at each visit as part of routine care. Symptomsincluded Anxiety, Depression, Irritability, Apathy, Fatigue, Body Pain,Insomnia, Headache, Psychosis, and Cognitive Disability were retrievedfrom the medical records. Besides individual scores ranging from 0-10per symptom, a total score ranging (0-100) was calculated.

Besides self-report symptom severity, the National Institute of HealthToolbox measurements were used to collect composite-level outcomes incognitive, emotional and psychosocial domains. These measures werechosen because they were designed specifically to provide valid,longitudinal assessment of neuropsychiatric symptoms in community-basedpopulations for children, adults and elderly. Specifically, measurementswere made using the NIH Toolbox Pattern Comparison Processing Speed andDimensional Change Card Sort, General Life Satisfaction, Meaning andPurpose, and Social Satisfaction tests.

Visit & Treatment Group Designation

All patients were assigned a baseline visit and two follow-up visits.The baseline visit was assigned as the closest visit before which thepatient started the treatment of interest. The first follow-up visit wasthe closest visit within approximately one month of starting themedication. The last follow-up visit was the last time point ofobservation on the treatment of interest. Three different treatmentswere compared: before and after telmisartan, before and after verapamil,and before and after combination treatment.

Medication Adherence

Medication adherence was confirmed by reviewing the medical recordincluding pharmacy records of administration as well as physician notes.

Weber Lateralization

As part of routine care, the Weber test was delivered to patients duringtheir initial and/or follow-up visits, depending on time availability inthe clinic. The lateralization of the Weber was used for this study as aproxy of normalization of functional connectivity in the auditoryfunctional network.

Statistics

A paired samples t-test was used to measure the significance of changesbefore and after treatment. Effect sizes were calculated using Cohen'smethodology and quantified using standard ranges signifying small (0.2to 0.5), medium (0.5 to 0.8) or large (above 0.8) effects of treatment.In addition, paired t-tests were used to compare outcomes betweendifferent doses of combination therapy. Subgroup analyses were performedfor individuals with baseline clinical anxiety of moderate (4 andabove), baseline clinical anxiety of severe (7 and above), baselineclinical cognitive disability of moderate (4 and above) and baselinecognitive disability of severe (7 and above). In a separate sensitivityanalysis, all visits for patients, rather than only before and aftervisits, were used to calculate average symptom severity Off medicationvs. On medication. To test the association between medication change andWeber lateralization, chi square analysis was performed. Treatment groupwas categorized as Change in Combination Treatment vs. No Change.Lateralization was rated as Left, Left Middle, Middle, Right Middle andRight. Data analysis was done using STATA (Stata/IC 16.1).

Other Embodiments

From the foregoing description, it will be apparent that variations andmodifications can be made to the invention described herein to adopt itto various usages and conditions. Such embodiments are also within thescope of the following claims.

The recitation of a listing of elements in any definition of a variableherein includes definitions of that variable as any single element orcombination (or subcombination) of listed elements. The recitation of anembodiment herein includes that embodiment as any single embodiment orin combination with any other embodiments or portions thereof.

All patents and publications mentioned in this specification are hereinincorporated by reference to the same extent as if each independentpatent and publication was specifically and individually indicated to beincorporated by reference.

What is claimed is:
 1. A method for treating panic disorder, socialanxiety disorder, or post-traumatic stress disorder in a subject in needthereof, the method comprising: administering to the subject atherapeutic combination comprising verapamil and telmisartan, whereinthe mass ratio of verapamil to telmisartan in the combination is betweenabout 2:1 and about 3:1, and wherein the effective amount of verapamilis between about 120 mg and about 360 mg and the effective amount oftelmisartan is between 40 mg and 180 mg.
 2. The method of claim 1,wherein the effective amount of verapamil is about 288 mg and theeffective amount of telmisartan is about 96 mg.
 3. The method of claim1, wherein the mass ratio of verapamil to telmisartan is about 3:1. 4.The method of claim 1, wherein verapamil and telmisartan are formulatedseparately or together.
 5. The method of claim 1, wherein administrationof the therapeutic combination is associated with an alteration incerebral blood flow is one or more of the telencephalon, thediencephalon, and the mesencephalon.
 6. The method of claim 5, whereinthe alteration in cerebral blood flow is associated with theestablishment of hemodynamic equilibrium in a region of the brain. 7.The method of claim 1, wherein verapamil and/or telmisartan is providedin an extended release formulation.
 8. A method for reducing a symptomof an anxiety disorder in a subject in need thereof, the methodcomprising: administering to the subject a therapeutic combinationcomprising verapamil and telmisartan, wherein the mass ratio ofverapamil to telmisartan in the combination is between about 2:1 andabout 3:1, wherein the effective amount of verapamil is between about120 mg and about 360 mg and the effective amount of telmisartan isbetween 40 mg and 180 mg, and wherein the administration is associatedwith a reduction in a symptom of an anxiety disorder selected from thegroup consisting of anxiety, depression, irritability, apathy, fatigue,body pain, insomnia, headache, psychosis, and cognitive disability. 9.The method of claim 8, wherein verapamil and/or telmisartan is providedin an extended release formulation.
 10. The method of claim 1, whereinthe administration is associated with a decrease in a symptom selectedfrom the group consisting of depression, irritability, apathy, fatigue,body pain, insomnia, headache, psychosis, and cognitive disability.